Seifert was raised in San Francisco and ushered at 49ers home games at Kezar Stadium while he attended San Francisco Polytechnic High School across the street. He attended the University of Utah, playing guard and linebacker for the Utes. He served as graduate assistant at his alma mater for a year before being hired as head coach of Westminster College in Salt Lake City at age 25, where he led the Parsons to a 3–3 record.
After working as an assistant at the University of Iowa, the University of Oregon, and Stanford University, Seifert was hired as head coach at Cornell University. He was fired after going 3–15 in two seasons. He then returned to Stanford in 1977, where he met Walsh. When Walsh moved to the 49ers in 1979, Seifert remained at Stanford for one more year before joining him.
As a 49er assistant, his defenses finished in the top ten in fewest points allowed in each of his six seasons in that capacity: fourth in 1983, first in 1984, second in 1985, third in 1986 and 1987, and eighth in 1988. His final two defenses, 1987 and 1988, finished first and third in fewest yards allowed, respectively. On his 49th birthday, the 49ers won the Super Bowl in 1989.
In 1989, he was elevated to head coach. He is one of only 13 NFL head coaches with more than one Super Bowl victory, winning in both the 1989 and 1994 seasons with the San Francisco 49ers. In Super Bowl XXIV he became the first rookie head coach to win the Super Bowl since Don McCafferty coached the Baltimore Colts to victory in Super Bowl V. In all, Seifert coached on five Super Bowl champion teams with the 49ers. Seifert was forced to resign after the 1996 season.
After two years out of the game, he was hired by the Carolina Panthers as head coach. He was also de facto general manager as well; the Panthers hadn't had a general manager since Bill Polian's departure in 1997.
In his first season, Seifert led the Panthers to an 8–8 record, a four-game improvement from 1998. The Panthers went into the final day of the regular season in contention for a playoff berth; however, their victory margin over the New Orleans Saints needed to be 18 points greater than the Packers' margin over the Arizona Cardinals in order to make the playoffs. While the Panthers routed the Saints 45–13, the Packers beat the Cardinals 49–24, leaving the Packers ahead on point differential and eliminating the Panthers.
The Panthers were competitive for most of 2000 as well, but needed to win their season finale against the Oakland Raiders to finish at .500, The Raiders defeated the Panthers by a score of 52–9, still one of the most lopsided losses in Carolina history. Seifert presided over the 2001 NFL Draft, which netted the Panthers Steve Smith and Kris Jenkins, two cornerstones of the franchise. Behind rookie quarterback Chris Weinke, they defeated the Minnesota Vikings, 24–13, in the 2001 season opener. However, they did not win another game all season and finished at 1–15, the worst record in franchise history. The 15 consecutive losses was an NFL record for futility until the 2008 Detroit Lions went 0–16. The Panthers's final two games were played before what are still the two smallest crowds in franchise history (in terms of turnstile count), including a 38–6 loss to the New England Patriots that drew only 21,000 people. Seifert was fired the next morning.