Essman began her acting career with small parts in two 1988 films – Crocodile Dundee II and Punchline – but is best known for her role as Susie Greene, the wife of Jeff Greene (portrayed by Jeff Garlin), on the HBO comedy series Curb Your Enthusiasm. Essman told The New York Times that, by the show's third season, she could not "walk down the street anymore without people stopping her and begging her to say [her character's catchphrase] 'You fat fuck'". In 2007, Slate named Essman's character one of the best on television, and a reason the publication looked forward to the return of the show.

Essman has been traveling and appearing at clubs throughout the country for more than two decades. She was a guest on The Tonight Show with Johnny Carson on January 5, 1989. Her first half-hour special appeared on Comedy Central in 1992. As much of her comedy draws from her ethnic background, she has been featured in such documentaries as, Heroes of Jewish Comedy and A History of Jewish Comedy.

Essman was born in The Bronx, New York City, and was raised in the middle-class New York City suburb of Mount Vernon. Her father, Leonard Essman, was an internist who died in 2001. Her mother, Zora (née Pressman), taught Russian at Sarah Lawrence College. Essman is Jewish; her grandparents emigrated from Russia and Poland. She received her bachelor's degree from SUNY Purchase College.

On October 15, 2004, she performed at the Friars Club roast of Donald Trump, in which she lampooned the tycoon with lines like "Donald, did you enjoy your meal? I heard your hair ordered the salmon" and "I'm so not your type. I'm smart, my boobs are real, and I speak English." Essman made her U.K. standup comedy debut at the Corn Exchange at the Newbury Comedy Festival in July 2007. While in England, she appeared on the British television show 8 Out of 10 Cats.

She also provided the voice of Helen Higgins on the Comedy Central series Crank Yankers; she was an occasional correspondent on the first season of the network's The Daily Show. She appeared on Comedy Central's Roast of Bob Saget on August 17, 2008 and provided the voice of "Mittens" (the cat) in the Disney animated film, Bolt, and reprised the role in the 2009 short Super Rhino. She also made an appearance on the Regis Philbin version of Million Dollar Password.

Essman's book, What Would Susie Say: Bullshit Wisdom About Love, Life and Comedy, was published in October 2009 by Simon & Schuster.

Essman is a pescatarian—"Not a moral thing," she explains, but "aesthetic"; chicken "grosses me out"—and "lives on sushi". She married Jim Harder, a commercial real estate broker, in September 2008. She owns a Shih Tzu named Sumo.