He played paper salesman Andy Bernard in the NBC sitcom The Office (2006–2013), and starred as Stuart "Stu" Price in The Hangover trilogy.

He provided his voice to the animated films, Everyone's Hero (2006), Monsters vs. Aliens (2009), The Lorax (2012), Captain Underpants: The First Epic Movie, Mune: Guardian of the Moon (both 2017) and Ron's Gone Wrong (2021).

He had open-heart surgery at age 13 to correct a severe congenital heart defect involving supravalvular aortic and pulmonic stenosis.

[11] Helms was performing comedy in New York City when, as he recalled in a 2005 interview, "The Daily Show had a sort of open audition with a casting company that I had dealt with.

[12] In his April 2002 to mid-2006 tenure on the satirical news program, Helms contributed "field reports" in addition to hosting various segments of the show such as "Digital Watch", "Ad Nauseam" and "Mark Your Calendar".

In late July 2006, NBC announced that Helms was added to the cast of the mockumentary The Office, alongside fellow The Daily Show correspondent Steve Carell, in a recurring role as Andy Bernard, a nostalgic Cornell graduate who is obsessed with a cappella music.

[14] "He had so much in common with this character we wanted to create," recalled Paul Lieberstein, a writer for the show who also plays Toby Flenderson, the human resources representative at the Scranton branch of Dunder Mifflin.

"[15] Helms returned to The Daily Show on December 5, 2006, saying that he had been working "undercover at a paper company in Scranton", an allusion to his stint on The Office.

He was the celebrity guest on the August 3, 2015 survival-skills reality show Running Wild with Bear Grylls, coming to grips with his fear of heights on the Colorado Mountains.

Ed Helms also voiced the titular character in the DreamWorks animated film named as Captain Underpants: The First Epic Movie (2017).

They recorded an eponymous album in summer 2013 shortly after appearing on the Bluegrass Situation stage at the Bonnaroo festival, which Helms curated.

It summarizes its mission as "Creating and covering content across every level of the international scene, ranging from timeless traditional bluegrass, blues, and old-time to contemporary singer/songwriter, Americana, folk, and everything rootsy beyond and in between.

[25] In 2024, Helms participated with his partner, Michael Falbo at Pacific Electric Picture Company, in SeriesFest 11's Storytellers Initiative to discover episodic content featuring uplifting and heartwarming comedies.

The script competition provides artists the opportunity to share diverse ideas through visual media and create groundbreaking television.

The winning artist(s) will receive the opportunity for a development deal with Pacific Electric Picture Co. Helms is a board member at RepresentUs,[26] a non-profit group that works to pass anti-corruption laws in the United States.