Landon was born in Forest Hills, a neighborhood of Queens, New York. Landon's father, Eli Maurice Orowitz, was a Jewish American actor and movie theater manager, and his mother, Kathleen Ignatius O’Neill, was an Irish American Roman Catholic dancer and comedienne. Landon was the Orowitz' second child; his sister, Evelyn, was born three years earlier. In 1941, when Landon was 4 years old, he and his family moved to Collingswood, New Jersey, where he later attended Collingswood High School.

After changing his name to Landon (selected from a phone book) he soon became one of the most popular and enduring young actors of the late 1950s, making his first appearance in The Mystery of Casper Hauser. This part led to other roles such as: I Was A Teenage Werewolf, Crossroads, The Rifleman, Fight For The Title, The Adventures of Jim Bowie, Wire Service, Telephone Time, General Electric Theater, The Court of Last Resort, The Tales of Wells Fargo, Johnny Risk, and The Legend of Tom Dooley, among many others.

In 1959, at age 22, Landon had his first starring TV role as Little Joe Cartwright on Bonanza, one of the first TV series to be broadcast in color. Landon's character was the green, cocky youngest Cartwright brother. The character evolved into a "ladies' man". During Bonanza's sixth season (1964-1965), the show topped the Nielsen Ratings and remained number one for three years. Landon, a southpaw, often performed his own stunts. Receiving more fan mail than any other cast member, the young actor successfully coaxed the powers-that-be to allow him to write and direct some episodes. It was a smart move, as he spent the next twenty plus years as one of television's most successful talents. In 1962, he wrote his first script. In 1968, he directed his first episode. In 1993, TV Guide listed Little Joe's September 1972 wedding episode, as one of TV's most memorable specials. Landon's script fondly recalled brother Hoss, who was initially the story's groom, before Dan Blocker's untimely death. During its final season, Bonanza declined in the ratings and NBC cancelled it in October 1972. Its last episode aired on January 16, 1973. Along with Lorne Greene, Landon appeared in all 14 seasons of the western. In 1962 Landon released a Bonanza related single, Gimme A Little Kiss/Be Patient With Me, on Columbia Records.

The year after Bonanza was canceled, Landon went on to star in the pilot of what would become another successful television series, Little House on the Prairie, again for NBC. The show was taken from a 1935 book that was published by Laura Ingalls Wilder, whose character in the show was played by then-unknown actress, Melissa Gilbert. Landon served as executive producer, writer, and director of Little House, making him a driving force in Hollywood. The show, a success in its first season, emphasized family values and relationships. Little House became Landon's second-longest running series. Above all, the entire cast shared a close bond with Landon, especially Gilbert.

Tremendously popular with viewers, the show was nominated for several Emmy and Golden Globe awards. After eight seasons, Little House was retooled by NBC in 1982 as Little House: A New Beginning, which focused on the Wilder family and the Walnut Grove community. The New Beginning was actually the final chapter of Little House, as the series ended the show's run in 1983. The following year, three made-for-television movies followed.

After producing both the Father Murphy TV series and a movie, Sam's Son, Landon went on to star in another successful television series. On Highway to Heaven, he played Jonathan Smith, a probationary angel whose job was to help people in order to earn his angel wings. His co-star on the show was Victor French (who previously co-starred on Landon's Little House on the Prairie) as ex-cop, Mark Gordon. NBC didn't feel the show would last very long, but it too proved to be another hit for Landon. This was also the first religious fantasy drama series, starting a specialized sub genre which included later shows such as Touched By An Angel. On Highway, Landon served as executive producer, writer and director of the show. Though Landon liked directing and writing more than acting, he continued to act because actors were paid more, and his top-billing enticed network executives to buy his series. Highway to Heaven was the only show throughout his long career in television that he owned outright.

Landon's shows were all on NBC, but after ending Highway, he moved to CBS and in 1991 starred in a two hour pilot called Us. This was meant to be another series for Landon, but on April 5, he was diagnosed with pancreatic cancer. Landon's heavy cigarette smoking—four packs a day—contributed to this cancer. On April 8, 1991, he appeared at a press conference to speak of his illness promising to do the best that he could to fight the cancer. In June 1991, Landon made the cover of Life Magazine, after giving the magazine an exclusive rare private interview in May about his life, his family, and his struggle to live. Less than 2 months later, on July 1, 1991, Landon died in Malibu, California, at the age of 54. A community building at Malibu's Bluffs Park was named The Michael Landon Center following the actor's death.