Lott graduated from the University of Southern California in 1981 with a degree in public administration. As a sophomore in 1978, he helped the Trojans to a share of the national championship with a win in the Rose Bowl; they finished second in the polls in 1979 and again won the Rose Bowl. Lott was a unanimous All-American and team captain in 1980, recording eight interceptions and 166 return yards. In 2002, he was inducted as one of 15 new members (I-A class) of the College Football Hall of Fame. He was also a 1995 inductee to the USC Athletic Hall of Fame.

Lott was selected in the first round (8th overall) of the 1981 NFL Draft by the San Francisco 49ers. 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 rookie season in 1981, 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 Giants linebacker Lawrence 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 while tackling running back Timmy Newsome, and a bone graft surgery would not have allowed him to start the 1986 season. An injury sidelined him for the season’s last two games in 1986, 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. Lott signed a free agent deal with the Kansas City Chiefs in 1995, 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 1994 and the 100th Anniversary Team in 2019.

In 1991, Lott, along with Jill Lieber, wrote an autobiography, Total Impact. Lott inspired the Lott IMPACT Trophy, which is given annually by the Pacific Club IMPACT Foundation to college football’s Defensive IMPACT Player of the Year. The 2011 winner was Boston College linebacker Luke Kuechly. 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. Lott is an avid fan of the San Jose Sharks. On February 17, 2015, he was appointed to the Board of Directors of GSV Capital Corporation, a publicly traded investment fund.

Lott turned to broadcasting following his retirement, serving as an analyst on Fox NFL Sunday in 1996 and 1997, and working on the network’s game coverage in 1998. He is currently on a show called PAC-12 Playbook on the Pac-12 Network, an American sports-oriented digital cable and satellite television network. He also serves on the Board of Selectors of Jefferson Awards for Public Service.