Company: DNLI
Filing Date: 2025-12-09
Form Type: 424B5
Source: 0001628280-25-056085
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Company: Denali Therapeutics Inc.
Filing Date: 2025-12-09
Form: 424B5
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#### Filed Pursuant to Rule 424(b)(5)

#### Registration No. 333-285326
The information in this preliminary prospectus supplement is not complete and may be changed. A registration statement relating to these securities has been filed with the Securities and Exchange Commission and is effective. This preliminary prospectus supplement and the accompanying prospectus are not an offer to sell these securities and they are not soliciting an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

#### Subject to Completion
<div align='center'>Preliminary Prospectus Supplement dated December 9, 2025</div>

#### PROSPECTUS SUPPLEMENT
(To prospectus dated February 27, 2025)

|                                                                   |     | Shares of Common Stock |
| Pre-Funded Warrants to Purchase            Shares of Common Stock |     |                        |

We are offering up to shares of our common stock and, in lieu of common stock to certain investors, pre-funded warrants to purchase up to shares of our common stock in this offering.

The purchase price of each pre-funded warrant equals the price per share at which shares of our common stock are being sold to the public in this offering, minus $0.01, which is the exercise price of each pre-funded warrant. The pre-funded warrants do not expire, and each pre-funded warrant will be exercisable at any time after the date of issuance. This prospectus supplement also relates to the offering of the shares of our common stock issuable upon the exercise of such pre-funded warrants.

Our common stock is quoted on the Nasdaq Global Select Market under the symbol “DNLI". On December 8, 2025, the last reported sale price of our common stock on the Nasdaq Global Select Market was $19.69 per share. There is no established public trading market for the pre-funded warrants, and we do not expect a market to develop. We do not intend to list the pre-funded warrants on the Nasdaq Global Select Market or any other national securities exchange or nationally recognized trading system.

#### Investing in our securities involves risks. See "

#### Risk Factors

#### " beginning on page

#### S- 7
of this prospectus supplement and in the documents incorporated by reference.

Neither the Securities and Exchange Commission nor any other regulatory body has approved or disapproved of these securities or passed upon the adequacy or accuracy of this prospectus supplement or the accompanying prospectus. Any representation to the contrary is a criminal offense.

|                                                        |     | Per Share |