One of the most heavily-touted prospects in the history of high school football, he was an offensive standout at Berwick High School. Powlus was named Parade Magazine prep player of the year and USA Today offensive prep player of the year in 1992. After Powlus signed his letter of intent with Notre Dame that year, ESPN analyst Beano Cook predicted that Powlus would win the Heisman Trophy twice. This was extremely high praise considering that only one player in the history of college football, Archie Griffin, had won the trophy twice.
Powlus was a two-time Irish captain who, before the ascent of Brady Quinn in 2005, held 20 school records. He started 42 of 44 regular-season games (Thomas Krug started in place of injured Ron Powlus during the end of the 1995 season plus the 1996 Orange bowl) in which he played for the Irish (plus two bowl games) and finished with 558 career completions on 969 attempts for 7,602 yards and 52 touchdowns. He set the Irish single-game mark for TD passes in a game with four (three times) and at one point completed 14 straight passes. He set single-season marks in 1997 as a senior with his 182 completions and 298 attempts.
Powlus rebounded from a broken collarbone suffered in the preseason of what would have been his freshman season in 1993 and then broke a bone in his upper left arm late in the 1995 season.
He also spent two years as executive assistant to the Democratic Policy Committee of the Pennsylvania State Senate where he worked alongside another former Northeastern Pennsylvania sports hero, Bishop Hannan sharpshooter TJ McNulty. He was later employed in the banking and pharmaceutical industries.
On March 1, 2005, Powlus returned to Notre Dame as the football team's director of personnel development under head coach Charlie Weis. Following the termination of Peter Vaas' contract, Powlus assumed Vaas' position as the team's quarterbacks coach. After the 2009 season, Powlus was fired along with nearly the entire Notre Dame staff by head coach Brian Kelly. After his departure from Notre Dame he reunited with another former Notre Dame coach, Rob Ianello, as the quarterbacks coach at the University of Akron. After being hired as the head coach at Kansas, Charlie Weis named Powlus his quarterbacks coach.