Lott was born in Albuquerque, New Mexico. He attended Frisbie Junior High and Eisenhower High School in Rialto, California, where he played football under Coach Bill Christopher and graduated in 1977. He considered his time at Eisenhower High School the best years of his life. It is commonly thought that he was the best player on his team, he started as a wide receiver in 1975 as a sophomore, started at wide receiver and safety in 1976 as a junior, and in 1977 he started at quarterback and safety. The football stadium was recently named after Lott, even though he never played in the stadium. Lott was also the winner of the 1977 Ken Hubbs Award, given to the greater San Bernardino, California area's top male high school athlete.
Upon entering USC, Lott and teammate and future NFL star Marcus Allen were both considered for the tailback and safety positions. After much consideration, head coach John Robinson asked Lott to play defense because he was a better tackler than Allen. He was also supposedly one of the reasons that USC teammate Riki Ellison got into the NFL after he and Jerry Attaway (their USC conditioning coach) convinced Bill Walsh to take a chance on him.
After college, Lott was drafted by the San Francisco 49ers in the first round (8th overall pick) of the 1981 NFL Draft. The level of skill demonstrated by the 6-foot, 203-pound standout was instantly recognized, and from the very beginning of training camp he had the job as the 49ers' starting left cornerback. In his first season, he recorded seven interceptions, helped the 49ers to win Super Bowl XVI, and also became only the second rookie in NFL history to return three interceptions for touchdowns. His outstanding play resulted in his finishing second for Rookie of the Year honors, behind New York GiantslinebackerLawrence Taylor.
Lott switched to the safety position in 1985. He had the tip of his left pinky finger amputated after the 1985 season when it was crushed by tackling running back Timmy Newsome, and a bone graft surgery wouldn't have him ready in time for the 1986 season. A 1986 injury sidelined him for the season's last two games, but he still led the league with a career-best 10 interceptions, while recording 77 tackles, three forced fumbles, and two quarterback sacks. In his 10 years with the 49ers, Lott helped them win eight division titles and four Super Bowls: XVI (1981 season), XIX (1984), XXIII (1988), and XXIV (1989). He is one of five players that were on all four 1980s 49er Super Bowl wins. The other four are quarterback Joe Montana, linebacker Keena Turner, cornerback Eric Wright, and wide receiver Mike Wilson.
After his career with San Francisco, Lott signed as a free agent in 1991 with the Los Angeles Raiders, and in 1993 with the New York Jets. In 1991, he led the league in interceptions (8) for a second time. In 1995, Lott signed a free agent deal with the Kansas City Chiefs, but was injured in the preseason. He returned to the 49ers in 1995, but the injuries he had suffered over the previous four seasons continued to plague him, and he announced his retirement before the season began. He was elected to the Pro Football Hall of Fame in 2000, his first year of eligibility, and was also named to the NFL's 75th Anniversary Team.
In his 14 NFL seasons, Lott recorded 8.5 sacks and 63 interceptions, which he returned for 730 yards and five touchdowns. He recovered 17 fumbles, returned them for 43 yards, and gained 113 yards on kickoff returns. Lott also played in 20 postseason games, recording nine interceptions, 89 tackles, one forced fumble, one fumble recovery, and two touchdowns. He was also named All-Pro eight times, All-NFC six times, and All-AFC once. Beyond statistics, Lott had an uncanny awareness of how a play was developing, which allowed him to break up passes and earn a reputation as one of the hardest and most efficient open-field tacklers in the history of the league.
Lott was the guest of honor at a CYO fundraiser at Sharon Heights Country Club in Menlo Park, CA in May 2012 where he discussed the importance of helping the community. Lott credits the late Coach Ben Parks as a central figure in the development of his vigorous philanthropic work.
On February 17, 2015 he was appointed to the Board of Directors of GSV Capital Corporation, a publicly traded investment fund.