TABLE OF CONTENTS Filed Pursuant to Rule 424(b)(5) Registration No. 333-238996 PROSPECTUS SUPPLEMENT (To Prospectus Dated June 15, 2020) Up to $100,000,000 American Depositary Shares representing Ordinary Shares In accordance with the terms of the Controlled Equity OfferingSM Sales Agreement, or sales agreement, dated as of June 5, 2020, with Cantor Fitzgerald & Co. and Oppenheimer & Co. Inc., or, collectively, the Sales Agents, we may offer and sell American Depositary Shares, or ADSs, representing our ordinary shares, having an aggregate offering price of up to an additional $100,000,000 from time to time through the Sales Agents pursuant to this prospectus supplement. Our ADSs are listed on the Nasdaq Global Select Market, or Nasdaq, under the symbol “BCYC.” On May 21, 2021, the last reported sale price of our ADSs was $30.71 per ADS. Sales of our ADSs, if any, under this prospectus supplement and the accompanying prospectus may be made in sales deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, or the Securities Act, including sales made directly on or through Nasdaq or any other existing trading market for our ADSs. The Sales Agents are not required to sell any specific number or dollar amount of securities. Neither of the Sales Agents is required to sell any specific number or dollar amount of securities, but each has agreed to use its commercially reasonable efforts to sell on our behalf all of the ADSs requested to be sold by us, consistent with its normal trading and sales practices, on mutually agreed terms among the Sales Agents and us. There is no arrangement for funds to be received in any escrow, trust or similar arrangement. The Sales Agents will be entitled to compensation at a commission rate of 3.0% of the gross sales price per ADS sold. See “Plan of Distribution” for additional information regarding compensation to be paid to the Sales Agents. In connection with the sale of the ADSs on our behalf, each of the Sales Agents will be deemed to be an “underwriter” within the meaning of the Securities Act, and the compensation of the Sales Agents will be deemed to be underwriting commissions or discounts. Investing in our securities involves a high degree of risk. Before buying any securities, you should review carefully the risks and uncertainties described under the heading “Risk Factors” on page S-5 of this prospectus supplement and under similar headings in the other documents that are incorporated by reference into this prospectus supplement and accompanying prospectus, as they may be amended, updated or modified periodically in our reports filed with the Securities and Exchange Commission. We are an “emerging growth company” as that term is used in the U.S. Jumpstart Our Business Startups Act of 2012 and, as such, have elected to comply with certain reduced public company reporting requirements for this prospectus supplement, the accompanying prospectus and future filings. Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or determined if this prospectus supplement or the accompanying prospectus is truthful or complete. Any representation to the contrary is a criminal offense. Cantor Oppenheimer & Co. The date of this prospectus supplement is May 24, 2021 TABLE OF CONTENTS TABLE OF CONTENTS Prospectus Supplement ABOUT THIS PROSPECTUS SUPPLEMENT S-1 PROSPECTUS SUPPLEMENT SUMMARY S-2 RISK FACTORS S-5 SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS S-8 USE OF PROCEEDS S-10 DILUTION S-11 PLAN OF DISTRIBUTION S-12 CERTAIN MATERIAL INCOME TAX CONSIDERATIONS S-14 LEGAL MATTERS S-22 EXPERTS S-22 WHERE YOU CAN FIND MORE INFORMATION S-22 INCORPORATION OF CERTAIN INFORMATION BY REFERENCE S-23 Prospectus ABOUT THIS PROSPECTUS ii PROSPECTUS SUMMARY 1 RISK FACTORS 7 SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS 8 USE OF PROCEEDS 10 DESCRIPTION OF SHARE CAPITAL AND ARTICLES OF ASSOCIATION 11 DESCRIPTION OF AMERICAN DEPOSITARY SHARES 28 DESCRIPTION OF DEBT SECURITIES 39 DESCRIPTION OF WARRANTS 45 DESCRIPTION OF UNITS 48 LEGAL OWNERSHIP OF SECURITIES 50 PLAN OF DISTRIBUTION 53 TAXATION 55 LEGAL MATTERS 55 EXPERTS 55 SERVICE OF PROCESS AND ENFORCEMENT OF JUDGMENTS 56 WHERE YOU CAN FIND MORE INFORMATION 58 INCORPORATION OF CERTAIN INFORMATION BY REFERENCE 59 TABLE OF CONTENTS ABOUT THIS PROSPECTUS SUPPLEMENT This prospectus supplement and the accompanying prospectus relate to part of a registration statement on Form S-3 (File No. 333-238996) that we filed with the Securities and Exchange Commission, or SEC, on June 5, 2020 utilizing a “shelf” registration process. Under this shelf registration process, we may sell any combination of the securities described in our base prospectus included in the shelf registration statement in one or more offerings up to a total aggregate offering price of $250,000,000. The additional $100,000,000 of ADSs that may be offered, issued and sold under this prospectus supplement is included in the $250,000,000 of securities that may be offered, issued and sold by us pursuant to our shelf registration statement. This prospectus supplement relates to the offering of our ADSs. Before buying any of the ADSs that we are offering, we urge you to carefully read this prospectus supplement and the accompanying prospectus, together with the information incorporated by reference as described under the headings “Where You Can Find More Information” and “Incorporation of Certain Information by Reference” in this prospectus supplement. These documents contain important information that you should consider when making your investment decision. This document is in two parts. The first part is this prospectus supplement, which describes the terms of this offering of ADSs and also adds to and updates information contained in the accompanying prospectus. The second part, the accompanying base prospectus dated June 15, 2020, including the documents incorporated by reference therein, provides more general information, some of which may not apply to this offering. Generally, when we refer to this prospectus, we are referring to both parts of this document combined. To the extent there is a conflict between the information contained in this prospectus supplement and the information contained in the accompanying base prospectus, you should rely on the information in this prospectus supplement. However, if any statement in one of these documents is inconsistent with a statement in another document having a later date — for example, a document incorporated by reference into this prospectus supplement — the statement in the document having the later date modifies or supersedes the earlier statement as our business, financial condition, results of operations and prospects may have changed since the earlier dates. You should rely only on the information contained in or incorporated by reference in this prospectus supplement, the accompany prospectus, and in any free writing prospectus that we have authorized for use in connection with this offering. We have not, and the Sales Agents have not, authorized anyone to provide you with different information. If anyone provides you with different or inconsistent information, you should not rely on it. We are not, and the Sales Agents are not, making an offer to sell these securities in any jurisdiction where the offer or sale is not permitted. You should assume that the information appearing in this prospectus supplement and the accompanying prospectus, the documents incorporated by reference herein and therein, and in any free writing prospectus that we have authorized for use in connection with this offering, is accurate only as of the date of those respective documents. Our business, financial condition, results of operations and prospects may have changed since those dates. You should read this prospectus supplement, the accompanying prospectus, the documents incorporated by reference herein and therein, and any free writing prospectus that we have authorized for use in connection with this offering, in their entirety before making an investment decision. You should also read and consider the information in the documents to which we have referred you in the sections of this prospectus supplement entitled “Where You Can Find More Information” and “Incorporation of Certain Information by Reference.” S-1 TABLE OF CONTENTS PROSPECTUS SUPPLEMENT SUMMARY This following summary highlights information about us, this offering and selected information contained elsewhere in or incorporated by reference into this prospectus supplement. This summary is not complete and does not contain all of the information that you should consider before deciding whether to invest in our ADSs. For a more complete understanding of our company and this offering, we encourage you to read and consider carefully the more detailed information in this prospectus supplement and the accompanying prospectus, including the information incorporated by reference, and the information included in any free writing prospectus that we have authorized for use in connection with this offering, including the information under the heading “Risk Factors” in this prospectus supplement on page S-5, in the accompanying prospectus, and in the documents incorporated by reference into this prospectus. Unless the context indicates otherwise, references in this prospectus supplement to “Bicycle,” “the Company,” “we,” “us,” “our” and similar references refer to Bicycle Therapeutics plc and its wholly owned subsidiaries. Company Overview We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycles, for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycles are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule.