Edward Harry Deezen was born in Cumberland, Maryland, the son of Irma and Robert Deezen. A class clown in his youth, Deezen started out with aspirations of becoming a stand-up Comedian, moving out to Hollywood within days of graduating high school in order to pursue a career. As a Comedian, he performed at least three times at The Comedy Store, though eventually decided to abandon stand-up and focus on acting after bombing his last act and having difficulty memorizing his routine. Deezen attempted stand-up one last time, however, when he appeared on an episode of The Gong Show in the mid-1970s, only to be gonged by singer-songwriter Paul Williams.

Deezen landed his first and perhaps best known role in the film Grease, playing nerdy student Eugene Felsnic, a part he won through a standard audition process. During Grease's post-production period, Deezen won another small role playing a bully in the low-budget independent science fiction movie Laserblast. Despite being his second film, Laserblast marked Deezen's screen debut when it was released in March 1978, three months before the theatrical release of Grease.

Following the massive success of Grease, Deezen found himself being cast in a string of high-profile comedy films playing similarly nerdy characters, including Robert Zemeckis' directorial debut I Wanna Hold Your Hand and Steven Spielberg's 1979 epic comedy 1941. Deezen was in such demand by 1979 that he was constantly having to turn down roles. At least two such notable instances were the characters of Eaglebauer in Rock 'n' Roll High School and Spaz in Meatballs, both of which Deezen turned down in order to film 1941.

In the mid-1980s, Deezen transitioned into voice acting, a change of pace he favored due to better pay and not needing to memorize dialogue. He started out lending his voice to animated feature films, including the voice of Donnie Dodo in Sesame Street Presents Follow That Bird and Snipes the Magpie in Don Bluth's 1991 film Rock-A-Doodle. According to a 2011 interview, Deezen unsuccessfully auditioned for the role of the title character in Robert Zemeckis's Who Framed Roger Rabbit, losing out to Comedian Charles Fleischer. He was also considered for the role of Judge Doom in the film along with several other actors that were considered but lost the role to Christopher Lloyd.

1983's WarGames marked the final mainstream film of Deezen's live-action acting career as he began working exclusively in independent film for the remainder of the 1980s, starting with his first starring role in the 1984 cult comedy Surf II: The End of the Trilogy, where he played the movie's antagonist, mad scientist Menlo Schwartzer.

1984 also saw the release of Revenge of the Nerds, the film that is generally credited with making the stock character of the stereotypical "nerd" a mainstay of teen films. Despite having arguably created the nerd archetype in such movies before, Deezen was not cast in the film. He remarked in an interview that he later asked the producers of Revenge of the Nerds why he hadn't been offered a role and was given the response that he was deemed "too geeky", whereas casting was instead just looking to dress "normal people" up as nerds. Despite this, Deezen says he is frequently "recognized" by strangers for being in the film.

Deezen regularly lends his voice to radio and television commercials. In the late 1990s, he provided the voice of Pop (of Snap, Crackle and Pop) in commercials for Rice Krispies cereal, and Nacho, the mascot for Taco Bell's kid's meals commercials, alongside Rob Paulsen as Dog. In 2011, Deezen was under consideration for succeeding Gilbert Gottfried as the voice of The Aflac Duck but did not win the role.

Following his cameo appearance as a security guard in the 1996 Leslie Nielsen spoof Spy Hard, Deezen wouldn't appear in a live-action film for another 17 years. In a July 2009 interview, Deezen talked about his struggle maintaining an acting career, saying "The truth is, it is extremely tough to sustain a career in Hollywood. It is tough enough ever getting work, just the sheer odds. I loved John [Badham] and Matthew [Broderick] and it would definitely be my pleasure to work with them again. Believe me, if the right role was there and available, I'd be there in a second".

In 2004, Deezen returned to the big screen once again under the direction of Robert Zemeckis to supply voice and motion capture performance for the blockbuster holiday film The Polar Express, playing the role of the nerdy "Know-It-All". He reprised this role for the subsequent video game.

Deezen is a huge fan of The Beatles, proclaiming himself to be their "biggest fan". He was interviewed as himself for the unreleased 2005 film Me and Graham: The Soundtrack of Our Lives, a documentary following two filmmakers searching the US and UK for the ultimate Beatles fan. For over a year his official website featured a difficult Beatles trivia quiz - devised by Deezen himself - with a $100 prize for anyone who could answer all the questions correctly. Deezen revealed in a later interview that nobody had ever claimed the prize.

Deezen is also a pop culture trivia buff, and since 2011 has been a contributing Writer to several trivia websites including mental floss, TodayIFoundOut.com and Neatorama.com. While most of Deezen's articles pertain to The Beatles and their members, he also regularly writes about such subjects as baseball, American history and classic comedy acts like The Three Stooges, the Marx Brothers and Martin and Lewis.

In 2012, Deezen starred in a live-action comedic short film entitled I Love You, Eddie Deezen. The plot revolves around a nerdy woman's cross-country journey to find the man of her dreams: Eddie Deezen. The short was released on November 19, 2012. The following year, Deezen returned to live-action movies in Fred Olen Ray's television film All I Want for Christmas, making a cameo as a supposed A-list action movie star being interviewed on a daytime talk show. In early 2015, Deezen did a cameo in a live-action comedy short film Flight Fright, playing a nervous airline Passenger. In late 2016, he starred with Larry (The Soup Nazi) Thomas and Caryn Richman in the short comedy The Love Suckers, which screened at the 2017 New York City International Film Festival.