Born in Queens and raised in the borough's middle class Forest Hills, Romano went to high school with Fran Drescher. After graduating in 1975, he worked at various jobs (gas station attendant, bank teller, futon deliveryman) while dabbling in comedy, making appearances at open mike nights at various clubs. In 1987, he decided to pursue stand-up full-time. Two years later he won $10,000 and priceless exposure in a New York comedy contest that jump-started his career. After his appearance with Johnny Carson, Romano was featured in HBO's "The 15th Annual Young Comedians Festival—hosted by Dana Carvey"—and went on to perform in several other comedy showcases.

David Letterman was so impressed with the comic's 1994 appearance on his talk show that he had his production company Worldwide Pants develop a sitcom based on Romano's observational family comedy. "Everybody Loves Raymond" (CBS, 1996-2005) was tailored to reflect Romano's upbringing and talents. He was cast as a married sportswriter with three children whose pushy mother (Doris Roberts), out-there father (Peter Boyle) and idiosyncratic brother (Brad Garrett) are neighbors, creating myriad complications for the young Barone family with their constant and bizarre intrusions. With relatable true-to-life dialogue, multidimensional characters and wacky, fact-based situations, "Everybody Loves Raymond" was a rare series, a family sitcom that managed to be fresh but not overly edgy. Described by many critics as "'Seinfeld' with kids,” the show lacked its predecessor's zany inhumanity and instead had a touching but skewed focus on relationships. "Everybody Loves Raymond" also steered clear of the grating preciousness all too common in family sitcoms, presenting scenes with children that were engaging and realistic, not saccharine and exploitative. While the network highly touted the sitcom and critics praised it, its Friday night time slot was hardly a ratings grabber.

A switch to Monday nights beginning in the 1997-1998 season proved just what the series needed, and the show built up an impressive audience despite competition from major contenders "Monday Night Football" (ABC) and "Ally McBeal" (Fox). Going from ratings rankings in the 80s to frequent appearances in the Top Ten, the flourishing sitcom finally won Emmy recognition in 1999, when Romano was nominated as producer and lead actor. The following year he repeated in those categories and also grabbed a writing nod, continuing his run of Lead Actor, Comedy Series nominations in 2001. A self-described "stand-up comedian with a day job,” Romano's acting skills increased as the series progressed, and Raymond Barone the TV character began to develop his own distinct quirky persona, actually winning the lead actor in a comedy trophy in 2002. A year later he would win an Emmy again as executive producer of "Raymond" when it was named best comedy series, an honor it earned again for the swansong season in 2005. In addition to appearing on numerous TV specials, Romano also portrayed Barone while making guest appearances on episodes of the CBS series "The Nanny" (1998), "The King of Queens" (1998, 1999, 2006) and "Becker" (1999).

Romano made his feature debut with a voice acting turn as a wooly mammoth in the animated "The Ice Age" (2002), then played a small town handyman who, to prove himself to his long-suffering girlfriend, runs for mayor against a former U.S. President (Gene Hackman) in the comedy "Welcome to Mooseport" (2004), and appeared the little-seen low-budget indie, "Eulogy" (2004), a dull and lifeless ensemble black comedy about an unhappy college student (Zooey Deschanel) who returns home to her hated family after the death of her grandfather (Rip Torn). Romano played her dimwitted Uncle Skip, a sleazy trial lawyer and father of two crude teenage sons who mimic his adolescent habit for leering. Meanwhile, Romano revived Manny the wooly mammoth for “Ice Age: The Meltdown” (2006), the wildly successful sequel that reunited Sid the sloth (John Leguizamo), Diego the saber-toothed tiger (Denis Leary) and Scrat the prehistoric squirrel (Chris Wedge) in a quest to find Manny a mate despite possibly being the last mammoth in their rapidly melting world. Returning to stand-up comedy, Romano was set to be seen in “95 Miles to Go” (2006), a road trip documentary that followed the comedian and opening act, Tom Caltabiano, on an eight day, thousand mile tour through the south.