Melamed's voice became a familiar presence on television, serving as the sound of the Olympics, Mercedes Benz, CBS Sports, USA Network, the Super Bowl, and numerous commercials and television programs. He became known within the industry as a voice actor, appearing in the Grand Theft Auto series, and dubbing several actors' entire performances in films. But it was for his portrayal of "sensitive" villain Sy Ableman, in Joel and Ethan Coen's 2009 film, A Serious Man, which was nominated for Best Picture at the 2010 Academy Awards, that he became most widely known. About that character, Film Confessional said, "Sy Ableman is as great a contemporary movie villain as The Joker, Hans Landa, or Anton Chigurh.... The character Fred Melamed contrives is the year's most brilliant force of destruction."

On Broadway in 2011, after a long hiatus from the theatre, Melamed originated the roles of The Father in Ethan Coen's Talking Cure, and Thomas Moran in Elaine May's George Is Dead, two of the one-act plays that comprised Relatively Speaking. Subsequently, Melamed took on the role of Vanya in the Guild Hall production of Uncle Vanya, about which The New York Times said he gave "... an excellent ... multi-layered performance ... Mr. Melamed easily inhabits the comic, awkward lover, but also brings out Vanya's vast loneliness ...".

Melamed's slate of upcoming films includes the Sundance film Lemon, a collaboration with Brett Gelman and Janicza Bravo, Brawl in Cell Block 99 opposite Vince Vaughn, Sean McGinly's Silver Lake, which he stars in with Martin Starr, and Dragged Across Concrete. Melamed recently starred as Sam in Lake Bell's In a World..., winner of the Waldo Salt Screenwriting Award at the Sundance Film Festival, opposite Kurt Russell and Richard Jenkins in Bone Tomahawk, and re-teamed with the Coen brothers and co-stars George Clooney, Tilda Swinton, and Ralph Fiennes in Hail, Caesar!. He starred previously in Get On Up, a bio-pic about the life of James Brown, and opposite Elliott Gould, as auteur/director Bob Wilson, in Fred Won't Move Out, a film about the decline of a stubborn patriarch and his family. Other recent films include The Dictator (2012), with Sacha Baron Cohen and Sir Ben Kingsley, where Melamed appears in a cameo as the Director of the dictator's Nuclear Weapons Program, and Some Kind of Beautiful, where Melamed plays a villain, opposite Pierce Brosnan and Jessica Alba. Melamed has also voiced cult-leader Cris Formage in the Grand Theft Auto video game series.

On television, Melamed stars with Maria Bamford in the Netflix comedy Lady Dynamite, on FX's Emmy Award-winning Fargo, Hulu's Golden Globe Award-nominated Casual, the Fox comedy New Girl, and Verizon Go90's Sports send-up Now We're Talking. He is a present or past recurring guest star on USA Network's Benched, Showtime's House of Lies, HBO's Girls, Childrens Hospital, Blunt Talk, FX's Married, and Trial & Error. In previous seasons, he played Larry David's smug Psychiatrist, Dr. Arthur Thurgood, on Curb Your Enthusiasm, tough-guy jurist Judge Alan Karpman on The Good Wife, and played himself in the CBS situation comedy The Crazy Ones with Robin Williams and Sarah Michelle Gellar. In 2017, he appeared as a special guest star in the acclaimed Fargo episode "The Law of Non-Contradiction". He also appeared in 2 episodes of Brooklyn Nine-Nine as author, DC Parlov.