Humphries was selected by the Redskins in the sixth round of the 1988 NFL Draft. He made his first pro start in 1990 in Phoenix against the Cardinals with regular starter Mark Rypien sidelined with an injury. Humphries went on to pass for 1,015 yards and three touchdowns in seven games in 1990. The following season, he won a Super Bowl ring with the Redskins as Rypien's backup.
Humphries was traded to the San Diego Chargers before the start of the 1992 season following a preseason injury to starting Chargers QB John Friesz. The two teams ran the same offense, allowing Humphries to quickly make an impact. He passed for 3,356 yards, which ranked fifth in the league in 1992. He helped lead the Chargers, who were 4-12 in 1991 and stumbled out to an 0-4 start in 1992, to finish with an 11-5 record, winning the AFC West and ending the Chargers' decade-long playoff drought. To this day, the 1992 San Diego Chargers are the only NFL team to make the playoffs after an 0-4 start. He played with a separated left shoulder in the 1992 AFC Wild-Card Game, a 17-0 win over the Kansas City Chiefs, their first home playoff game since the 1980 AFC Championship game. Their season ended the next week in a 31-0 loss to the Miami Dolphins in the AFC Divisional Playoffs.
In 1994, Humphries led the Chargers with clutch performances through an impressive series of victories in the NFL Playoffs. It started with the Chargers rallying from a 21-6 halftime deficit at home to defeat the Miami Dolphins (led by Hall of Fame quarterback Dan Marino) with a 22-21 victory in the AFC divisional playoffs, earning the Chargers a trip to the AFC Championship Game the next week at Pittsburgh. The Pittsburgh Steelers were favored by 101⁄2 points, and some Steeler players the week prior to the game had made a Super Bowl rap video, assuming they would be the ones going to the Super Bowl. In what would become one of pro football's all-time great upsets, the Chargers again rallied from a 13-3 deficit late in the 3rd quarter and held off a furious last-minute Pittsburgh drive with a goal-line stand to win the AFC championship 17-13 at Pittsburgh's Three Rivers Stadium. Thus the Chargers earned a trip to Miami and Super Bowl XXIX, the first and only Super Bowl appearance in franchise history. Humphries executed the first successful two-point conversion in the Super Bowl (which was adopted by the NFL at the start of the 1994 season), throwing a pass to Mark Seay. They were greeted by 70,000 fans at San Diego Jack Murphy Stadium upon arriving back from Pittsburgh. Despite losing Super Bowl XXIX to the San Francisco 49ers 49-26, more than 100,000 fans greeted the Chargers when they arrived back in San Diego after the game.
In 1997, Humphries was forced to retire after a series of concussions. During his career, he led the Chargers to three playoff appearances and the franchise's only Super Bowl appearance. Humphries started for San Diego for six years, making 81 starts in 88 games while completing 1,431 of 2,516 passes for 17,191 yards and 89 touchdowns. San Diego was 47-29 (62 percent) in regular-season games and 3-3 in playoff contests he started from 1992 to 1997. He was inducted into the San Diego Chargers Hall of Fame in 2002. In 2009, he was one of four quarterbacks named on the franchise's 50th anniversary all-time team. In 2004, Humphries was also inducted by the San Diego Hall of Champions into the Breitbard Hall of Fame honoring San Diego's finest athletes both on and off the playing surface. He was inducted into the Louisiana Sports Hall of Fame in 2007.
Humphries is currently a commentator for college football. He also hosts his namesake celebrity golf tournament, which has raised more than $1 million over the years for Rady Children's Hospital in San Diego.