Dershowitz was a member of the legal defense team for the first criminal case against Jeffrey Epstein, who was investigated after accusations that he had repeatedly solicited sex from minors.[38] Dershowitz had previously befriended Epstein through their mutual acquaintance Lynn Forester de Rothschild.[10]

The first investigation into Epstein concluded with a controversial non-prosecution agreement that Dershowitz helped negotiate on Epstein's behalf.[10] On June 30, 2008, after Epstein pleaded guilty to a state charge (one of two) of procuring for prostitution a girl below age 18, he was sentenced to 18 months in prison.[39]

Beginning in 2015, Dershowitz was involved in a series of defamation lawsuits and countersuits over allegations that he engaged in sexual misconduct alongside Epstein. The suits were settled in 2022, with his accuser, Virginia Giuffre, saying, "I now recognize I may have made a mistake in identifying Mr. Dershowitz".[40][41]

In 2025, Dershowitz said he was aware of the names associated with the Epstein list but bound by confidentiality.[42] In 2025 it was reported that Dershowitz had contributed to the Jeffrey Epstein's 50th birthday greeting album with a mocked up fictional excerpt from Vanity Fair magazine.[43] According to Bloomberg Epstein gave Dershowitz's wife a new Lexus as a gift. Dershowitz described this as part of his legal fee as his wife would drive Epstein around.[44]