While attending Broad Ripple High School, he was a stock boy at Atlas Supermarket. Heading off... to college, he studied radio and television at Ball State University in Muncie, IN, and graduated with a B.A. in 1969. Letterman stayed in Indiana and worked as a radio talk show host, the host of a children's program called Clover Power, a late-night movie host, news anchor, and a television weather man. In 1975, he moved to L.A. and wrote for the TV show Good Times and developed a comedy routine that debuted at Mitzi Shore's Comedy Store.

Soon after, he began appearing on Mary Tyler Moore's variety show and then on NBC's Tonight Show With Johnny Carson. By 1978, he was Carson's regular guest host, which led to his hosting a daytime show, The David Letterman Show. While it only lasted three months, it did garner some critical accolades (and brought out the first Stupid Pet Tricks segment) and resulted in Letterman winning a spot for his own show following Carson's. Late Night With David Letterman first aired on February 1, 1982, and featured the first renditions of TV history fixtures like the Top Ten List and Viewer Mail.

Skits called for various parts to be filled and even spawned would-be comedians out of Letterman's sidekick/musical director of 19 years, Paul Shaffer, stage manager Biff Henderson, and Larry "Bud" Melman (or Calvert DeForest, as he is now called thanks to network politics). As Carson wound down his late-night reign, Letterman was hopeful he would be asked to take over the coveted spot. However, in 1993, comedian Jay Leno was chosen to succeed Carson instead. Feeling slighted, Letterman put aside his disappointment at not fulfilling a life-long dream of carrying on in his mentor's timeslot and moved to CBS to head up his own show. In turn, his move to CBS, which opened the 12:30 slot for another late-late-night hopeful, Conan O'Brien. In preparing for his new home, NBC told Letterman he couldn't use certain bits from his show on CBS as they were "intellectual property" of NBC. Luckily, most of the rights belonged to the writers/creators of those skits, so the tradition of Stupid Pet Tricks and so on could continue. The first episode of the newly named Late Show With David Letterman aired on August 30, 1993, and ran opposite Leno, causing a ratings battle ever since.

In what was named the late-night wars beginning with Leno's selection over Letterman, the situation created much discussion, speculation, and even a 1996 movie from HBO. The Late Shift, based on a non-fiction book by Bill Carter, depicted the drama behind who was to be chosen to take over for Carson. Although Letterman's audience is familiar with his driving record as it is the butt of many jokes, not much else is known about his personal life. He was married to Michele Cook from 1969 to 1977 and reportedly has a long-time girlfriend. Letterman introduced viewers to his mom via the 1994 Olympic Winter Games when she served as a correspondent and she has periodically appeared on the show ever since. For all his dry sarcasm, Letterman has occasionally shown a warmer, sensitive side. On January 14, 2000, he had quintuple bypass surgery. Along with his usual humor, upon his return to the show on February 21, he brought out the medical team that performed the surgery and gave them a teary, heartfelt thank you.

This side came out again when new episodes of his show went back on the air a week after the events of September 11, 2001. Instead of starting with the typical monologue, Letterman sat at his desk and simply stated: "If you didn't believe it before, you can believe it now: New York City is absolutely the greatest city on earth." Other than television appearances, he has played himself in a few movies, including the Andy Kaufman biopic Man on the Moon and Howard Stern's Private Parts, and some of his standup comedy can be found on The Comedy Store 20th Birthday. One character performance went uncredited, but is well known to Letterman fans nonetheless. In Chris Elliot's Cabin Boy, he plays a sarcastic villager Elliot's character encounters during a port stop. Along with hosting his own show, he also hosted the 1994 Academy Awards, where he came up with his famous introduction skit "Uma, Oprah. Oprah, Uma." Most celebrities pay the price for their fame by giving up their private lives. While Letterman does well to guard his, he couldn't keep one over-adulate fan at bay. Stalker Margaret Ray claimed on several occasions to be Letterman's wife and the mother of his (fictional) son. She had broken into his Connecticut home on a few occasions and had served ten months in prison and 14 months in a mental institution in relation to these violations. In October of 1996, she committed suicide by kneeling in front of an ongoing train in Colorado. Oddly enough, Letterman went back to work for NBC in 2000 by serving as an executive producer of the network's comedy-drama Ed. He is also the co-owner and founder of the Worldwide Pants production company, which also produces CBS's hit comedy Everybody Loves Raymond. In March 2002, ABC was looking to get rid of its news program Nightline, hosted by Ted Koppel and replace it with Letterman's show. After much speculation, Letterman decided to stay at CBS, but not without voicing his own support of veteran newsman Koppel.

In November 2003 Letterman became a father at the age of 56 when his girlfriend Regina Lasko gave birth to a son, Harry Joseph Letterman, named in honor of Letterman's late father.