Guttenberg was born in Brooklyn, New York, the son of Ann Iris (née Newman), a surgical assistant, and Jerome Stanley Guttenberg, an electrical engineer. He had a Jewish upbringing in the Flushing neighborhood of the borough of Queens before his family moved to North Massapequa, New York, where he graduated from Plainedge High School in 1976. During high school, he attended a summer program at the Juilliard School where he studied under John Houseman, and he won a role in an off-Broadway production of The Lion in Winter. After his high school graduation, he attended the State University of New York (SUNY) at Albany for a year. He moved to California to pursue an acting career. As Guttenberg recounts, within weeks he was cast in a Kentucky Fried Chicken commercial playing opposite Colonel Sanders.

After playing an uncredited bit part in Rollercoaster, Guttenberg had his first screen credit in the TV movie Something for Joey (1977). He then played the starring role in the 1977 California high school comedy The Chicken Chronicles, set in Beverly Hills in 1969. He also appeared in the 1978 film The Boys From Brazil, based on the Ira Levin best seller, and guest starred on the show Family. Guttenberg starred in the short-lived TV series Billy (1979), based on Billy Liar. He had a supporting role in the tennis romance film Players (1979). In 1980, a Coca-Cola commercial featured him trying to help a non-English-speaking woman whose car stalled.

Guttenberg married model Denise Bixler on September 30, 1988. They separated in June 1991 and divorced in 1992.

Guttenberg had the biggest financial success of his career to date with Three Men and a Baby (1987) with Tom Selleck and Ted Danson. He supported Peter O’Toole and Daryl Hannah in High Spirits (1988), which flopped. Cocoon: The Return (1989) was a commercial disappointment as was Don’t Tell Her It’s Me (1990). 3 Men and a Little Lady (1990) however was a hit. In 1989 he appeared in the Michael Jackson music video “Liberian Girl”.

In 1990 he replaced Timothy Hutton in the lead role of Prelude to a Kiss at the Helen Hayes Theatre on Broadway. He also performed in London’s West End, where he starred in The Boys Next Door. He appeared in the world stage premiere production of Furthest From the Sun, which Woody Harrelson directed and co-authored.

He directed “Love Off Limits” for CBS Schoolbreak Special in 1993 and starred in The Big Green (1995) in England. He was among the ensemble in Home for the Holidays (1995) and starred in It Takes Two (1995) with Kirstie Alley and Mary-Kate and Ashley Olsen. He also starred in Zeus and Roxanne (1997), Casper: A Spirited Beginning (1997) and alongside Kirsten Dunst in Disney’s Tower of Terror (1997), based on the attraction at the Disney’s Hollywood Studios at the Walt Disney World Resort in Lake Buena Vista, Florida. In the late 90s he made some action films, Airborne (1998) and Overdrive (1998) and the comedy Home Team (1998).

His first film as director/producer/co-screenwriter/star was P.S. Your Cat Is Dead (2002), a film adaptation of a novel and Broadway play by James Kirkwood, Jr.. He starred in Mojave Phone Booth (2006) as Barry, and Making Change as Trafton. In Single Santa Seeks Mrs. Claus and its sequel Meet the Santas, he played the starring role of Nick. He had a recurring role on the 2005-2006 season of the television series Veronica Mars as Woody Goodman, a wealthy businessman and community leader. He appeared as a lead in the NBC made-for-TV remake of The Poseidon Adventure, which aired on November 20, 2005, playing Richard Clarke, a failing writer having an affair with a massage therapist. He also appeared in According to Jim episode “Two for the Money” in 2008

On August 25, 2008, Guttenberg released a video titled “Steve Guttenberg’s Steak House” on funnyordie.com. Guttenberg took part in the 2008 spring season of Dancing with the Stars with professional pro Anna Trebunskaya and was eliminated on April 1. During an interview on November 4, 2009, Guttenberg mentioned that Disney was developing a second sequel to Three Men and a Baby, entitled Three Men and a Bride. Guttenberg stated that his co-stars, Ted Danson and Tom Selleck, would return for the sequel. Guttenberg also mentioned how he would like to make another Police Academy and Cocoon movie, saying they are surefire hits if they were to be made.

Guttenberg starred in the Cinderella pantomime at Churchill Theatre in Bromley, UK, playing the Baron (father of Cinderella) in 2008. To celebrate Guttenberg’s involvement, the local Empire Cinema screened Police Academy on 19 November. Guttenberg introduced the film and answered questions. On November 12, Guttenberg appeared as a guest on the British talk show The Paul O’Grady Show, he said he made the video for Will Ferrell’s Funny or Die website, but then decided to release it virally “as if it were real”. As part of challenge set on the show, he then went on to become the Guinness World Record Holder for preparing the most hot-dogs in one minute.

Guttenberg also played himself in an episode of the Starz comedy Party Down that originally aired May 21, 2010. Guttenberg starred in Season 7 Episode 6 of Law & Order: Criminal Intent (air date: November 8, 2007) He appeared on Broadway in late 2011 to early 2012 in Woody Allen’s one-act play “Honeymoon Hotel” which was part of the show Relatively Speaking. Guttenberg can be seen on History Channel’s 2015 miniseries Sons of Liberty. He plays Jack Bonner. In Fall 2014, Guttenberg wrapped production on SyFy Channel’s Lavalantula, scheduled to premiere Summer 2015. Guttenberg was also featured in the Season 6, Episode 8 of Community, “Intro to Recycled Cinema”, which aired on Yahoo Screen in April 2015.

On December 12, 2011, Guttenberg received a star on the Hollywood Walk of Fame. The star is located at 6411 Hollywood Blvd. On October 19, 2014, Guttenberg received a key to the city from Miami Beach Mayor Philip Levine for his work with Fun Paw Care, raising awareness for animal rights.

Guttenberg is involved with charities whose goal is to improve opportunities for the homeless and for young people. In 2016, a trust in Guttenberg’s honor was established to provide support services to the homeless population of Los Angeles. The Entertainment Industry Foundation, Hollywood’s charity arm, selected him to be Ambassador for Children’s Issues because of his work on behalf of children and the homeless.

At the 2016 New York Walk to Fight Lymphedema & Lymphatic Diseases in Brooklyn, Guttenberg announced via a pre-recorded message, that he had joined the Lymphatic Education & Research Network’s (LE&RN) Honorary Board.

Guttenberg has lived with WCBS-TV reporter Emily Smith since 2014. On December 25, 2016, the couple announced their engagement. The couple married on January 19, 2019.

On September 3, 2018, Guttenberg told a fan on Twitter that a new Police Academy film was being planned.

On May 21, 2020, Guttenberg appeared on Holey Moley II: The Sequel

On August 2, 2020, Guttenberg appeared on Last Week Tonight with John Oliver, via Cameo (website).