Murphy is also a singer, having frequently provided background vocals to songs released by The Bus Boys; the song "(The Boys Are) Back in Town" was featured in 48 Hrs. and Murphy's comedy special Eddie Murphy Delirious. As a solo Artist, Murphy had two hit singles, "Party All the Time" (which was produced by Rick James) and "Put Your Mouth On Me" during the latter half of the 1980s. He had started singing earlier in his career, with the songs "Boogie in Your Butt" and "Enough Is Enough", the latter being a parody of Barbra Streisand and Donna Summer's 1979 song, "No More Tears" (They both appear on his 1982 self-titled comedy album.)

In 1982, Murphy made his big screen debut in the film 48 Hrs. with Nick Nolte. 48 Hrs. proved to be a hit when it was released in the Christmas season of 1982. Nolte was scheduled to host the December 11, 1982, Christmas episode of Saturday Night Live, but became too ill to host, so Murphy took over. He became the only cast member to host while still a regular. Murphy opened the show with the phrase, "Live from New York, It's the Eddie Murphy Show!" The following year, Murphy starred in Trading Places with fellow SNL alumnus Dan Aykroyd.

In 1984, Murphy appeared in Best Defense, co-starring Dudley Moore. Murphy, who was credited as a "Strategic Guest Star", was added to the film after an original version was completed but tested poorly with audiences. Best Defense was a major financial and critical disappointment. When he hosted SNL, Murphy joined the chorus of those bashing Best Defense, calling it "the worst movie in the history of everything". Aykroyd originally wrote the Winston Zeddemore character in Ghostbusters specifically for Murphy, but he was unable to commit at the time due to the Beverly Hills Cop shooting schedule. The part ultimately went to Ernie Hudson.

"Party All the Time" was featured on Murphy's 1985 debut album How Could It Be, which included a minor follow-up R&B hit in the title track, a duet with vocalist Crystal Blake. This track was written by Rusty Hamilton and was produced by Stevie Wonder's cousin Aquil Fudge after a brief falling out with Rick James. In 2004, VH-1 and Blender voted "Party All the Time" number seven among the "50 Worst Songs of All-Time." Sharam used a sample of the song for the UK #8 hit "PATT (Party All The Time)" in 2006. "Put Your Mouth on Me" appeared on Murphy's 1989 follow-up album, So Happy.

In 1986, Murphy starred in the supernatural comedy, The Golden Child. Although The Golden Child performed well at the box office, the movie was not as critically acclaimed as 48 Hrs., Trading Places, and Beverly Hills Cop. The Golden Child was considered a change of pace for Murphy because of the supernatural setting as opposed to the more "street smart" settings of Murphy's previous efforts. A year later, Murphy reprised his role of Axel Foley in the Tony Scott-directed Beverly Hills Cop II. It was a box-office success, grossing almost $300 million worldwide.

In 1988, Art Buchwald sued Murphy and Paramount Pictures, alleging that they had used ideas from a screenplay he had submitted to Paramount as the basis for Murphy's film Coming to America. In 1992, Buchwald was awarded $150,000 in a summary judgment; Buchwald's producing partner, Alan Bernheim, was awarded $750,000. Both sides described the outcome as a "victory".

Murphy has a son, Eric (born circa 1989), with then girlfriend Paulette McNeely, and a son, Christian (born circa 1990) with then girlfriend Tamara Hood.

Murphy recorded the album Love's Alright in the early 1990s. He performed in a music video of the single "Whatzupwitu", featuring Michael Jackson. He recorded a duet with Shabba Ranks called "I Was a King". In 1992, Murphy appeared in Michael Jackson's "Remember the Time" alongside Magic Johnson and Iman.

Murphy began a longtime romantic relationship with Nicole Mitchell after meeting her in 1988 at an NAACP Image Awards show. They lived together for almost two years before getting married at the Grand Ballroom of The Plaza Hotel in New York City on March 18, 1993. Murphy and Mitchell had five children together: Bria, Myles, Shayne, Zola, and Bella. In August 2005, Mitchell filed for divorce, citing "irreconcilable differences". The divorce was finalized on April 17, 2006.

Dreamgirls was the first film distributed by Paramount Pictures to star Murphy (who once was on an exclusive contract with the studio) since Vampire in Brooklyn in 1995.

On May 2, 1997, Murphy was stopped by police after having been observed picking up a transgender prostitute. The prostitute, Shalimar Seiuli, was arrested on an outstanding warrant for prostitution. Murphy was not arrested or charged and claimed he was just giving Seiuli a ride.

Although Murphy has enjoyed commercial success since Saturday Night Live, he did not participate in the making of the Live From New York: An Uncensored History of Saturday Night Live retrospective book by Tom Shales and James Andrew Miller (2002), nor did he ever attend cast reunions or anniversary specials until his appearance on the SNL 40th anniversary special. Murphy's box office results began to recover in 1996, starting with The Nutty Professor.

In 2006, he starred in the motion picture version of the Broadway musical Dreamgirls as soul singer James "Thunder" Early. Murphy won a Golden Globe for Best Supporting Actor, as well as a Screen Actors Guild Award and a Broadcast Film Critics Association Award in that category. Several reviews for the film highlighted Murphy's performance while he received some pre-release Academy Awards buzz.

Following his divorce from Mitchell, in 2006, Murphy began dating former Spice Girl Melanie Brown, who became pregnant and stated that the child was Murphy's. When questioned about the pregnancy in December 2006, by RTL Boulevard, Murphy told Dutch reporter Matthijs Kleyn, "I don't know whose child that is until it comes out and has a blood test. You shouldn't jump to conclusions, sir". Brown gave birth to a baby girl, Angel Iris Murphy Brown, on Murphy's 46th birthday, April 3, 2007. On June 22, 2007, representatives for Brown announced in People that a DNA test had confirmed that Murphy was the father. Brown had stated in an interview that Murphy has not sought a relationship with Angel, although it was later reported in 2010 that Murphy was getting to know her.

Murphy exchanged marriage vows with film Producer Tracey Edmonds, former wife of Kenneth "Babyface" Edmonds, on January 1, 2008, in a private ceremony on an island off Bora Bora. On January 16, 2008, the couple released a statement saying, "After much consideration and discussion, we have jointly decided that we will forgo having a legal ceremony as it is not necessary to define our relationship further," and called the Bora Bora wedding a "symbolic union". The two had planned on having a legal ceremony upon their return to the U.S. but did not, and their wedding was never official.

Murphy co-starred in Tower Heist, directed by Brett Ratner. Murphy played a thief who joins a group of hardworking men who find out they have fallen victim to a wealthy businessman's Ponzi scheme, and conspire to rob his high-rise residence. Ben Stiller, Matthew Broderick, and Casey Affleck also starred in the film, released on November 4, 2011. It was reported in 2011 that Murphy would host the 84th Academy Awards in 2012. However, he dropped out of his hosting duties on November 9, 2011, in the wake of the Brett Ratner scandal.

On December 6, 2013, it was announced that Murphy would star in the fourth film of the Beverly Hills Cop series. Brett Ratner will direct the film, Jerry Bruckheimer is confirmed to produce the film, and Josh Appelbaum and Andre Nemec will write. In a June 2014 interview, Murphy discussed the plot of the film stating that it would take place in Detroit and they would actually film in Detroit bringing in an estimated $56.6 million to the state of Michigan. On June 14, 2016, it was confirmed that Murphy was still set to reprise his role as Axel Foley in a fourth film of the Beverly Hills Cop franchise.

On March 8, 2014, it was announced that Murphy would team up with Boomerang co-star Halle Berry in a new film titled Miles And Me. The film was also set to star Laurence Fishburne and was set to begin pre-production in 2014 from Paramount Pictures. No other word was released about or who else was attached.

On March 15, 2015, it was announced that Murphy will play Comedian Richard Pryor's father, LeRoy Pryor, in the upcoming biopic directed by Lee Daniels with Mike Epps playing Pryor.

Murphy began dating model Paige Butcher in 2012. Their daughter Izzy was born May 3, 2016.