Mainieri began his coaching career in Florida as the head coach of St. Thomas University in 1983. In six seasons, his team went 179–121–2, and Mainieri became the winningest coach in St. Thomas History. His No. 1 jersey was retired by the university in February 2012. In 2013, the new field at St. Thomas University was named in his honor. The Bobcats' new field is called Paul Demie Mainieri Field at Frank R. Esposito Stadium. Paul Mainieri asked the university to include his middle name, Demie, in the naming of the field because it is the same name as his father's first name. Both Mainieris have deep roots with St. Thomas, and recently became the first father-son duo to be elected to the American Baseball Coaches Association Hall of Fame. Mainieri was inducted into the St. Thomas Hall of Fame on November 1, 2009. Mainieri became the sixth person to be inducted into the St. Thomas Hall of Fame, joining Ken Stibler, Marinka Bisceglia, Manny Mantrana, Laura Courtley-Todd and John Batule.
Air Force
He moved on to the United States Air Force Academy in 1989, where he would also remain for six seasons. He became the second-winningest coach in Air Force history posting a mark of 152–158.
Mainieri replaced Smoke Laval at the end of the LSU Tigers' 2006 season. In the 2007 season, LSU finished 29–26–1 and did not reach the NCAA Tournament. 40 games into the 2008 season, the Tigers were again struggling with a 23–16–1 record. However, the team then went on a Southeastern Conference record 23-game win streak and moved on to claim the 2008 SEC Tournament Championship. Under Mainieri's leadership, the team swept the Baton Rouge Regional bracket of the NCAA baseball post-season and won their first Super-Regional since 2004. UC Irvine ended the streak in the first game of the Super Regional, defeating LSU 11–5, but LSU won the next two games and reached the 2008 College World Series. It was LSU's first College World Series appearance since 2004 and they recorded their first win since their CWS championship in 2000. Mainieri's Tigers entered the 2009 season as the favorites to win the SEC, and were the preseason No. 1 team in some national polls. During the season, the Tigers won the SEC regular season title, the 2009 SEC Tournament Championship, and reached the 2009 College World Series as the No. 3 national seed. Mainieri then led LSU to the CWS Finals against Texas. The Tigers won the first game 7–6 in 11 innings, lost the second 5–1, but won the national championship defeating the Longhorns 11–4 in the final game. The Tigers finished the season with a 56–17 record. Mainieri received the 2009 Coach of the Year award from Collegiate Baseball Newspaper and the 2009 Coach of the Year award by Baseball America. Rivals.com also named Mainieri the 2009 National Coach of the Year. The 2009 title was the sixth in LSU baseball history, tying Texas for the second most national championships in college baseball history, and Mainieri joined Skip Bertman as the only LSU baseball coaches to win a national championship. In 2015, Mainieri received the National Coach of the Year award from the National Collegiate Baseball Writers Association and the Skip Bertman Award presented by the College Baseball Foundation. During the 2017 season, LSU played Florida in a best-of-three series to determine the winner of the 2017 College World Series. Florida defeated LSU and the Tigers finished as College World Series runner-up.