The decision was issued by the Manhattan-based 2nd US Circuit Court of Appeals.
Maxwell, 62, has been serving a 20-year prison sentence after being convicted in 2021 on five charges for having recruited and groomed four underage girls for Epstein to abuse between 1994 and 2004.
Epstein was once Maxwell's boyfriend.
Epstein, 66, was found dead in his jail cell in August 2019 while awaiting trial for sex trafficking.
Maxwell's appeal focused in significant part on a 2007 non-prosecution agreement between Epstein and federal prosecutors in southern Florida, which she said barred her from being prosecuted in Manhattan 13 years later.
Her lawyer argued that references in Epstein's agreement to the "United States" signalled the government's intent to bar prosecutions country-wide of "potential co-conspirators" including four named in the agreement.
Maxwell was not among them.
A prosecutor countered that the mention of the United States was a throwaway reference, and Epstein's agreement was intended to bind only prosecutors in southern Florida.
In addition, Maxwell argued in her appeal that prosecutors scapegoated her because Epstein was dead and the public demanded that someone else be held accountable.
She also said her trial was tainted because one juror did not disclose that he had been sexually abused as a child.
Epstein ultimately pleaded guilty in 2008 to a Florida state prosecution charge and served 13 months in jail, an arrangement now widely considered too lenient.
His victims have since recouped hundreds of millions of dollars from his estate and from banks accused of handling transactions that financed his sexual misconduct.
The scandal has stained or destroyed the reputations of former friends including Prince Andrew and onetime Barclays CEO Jes Staley.
Maxwell has been serving her sentence in a low-security prison in Tallahassee, Florida.
She is eligible for release in July 2037.
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