The Jaguars (4-3) entered Sunday's game ranked 29th in passing at 169.7 yards per game, but surpassed that average by 160.3 yards against a banged-up Colts secondary.
Indianapolis (2-5) was shut out for the first time since a 41-0 playoff loss in 2002 at the New York Jets.
Bortles had a terrific first half, completing 14 of 20 passes for 282 yards and one touchdown. His first-half success included completions of 45, 50, 52, 24 and 28 yards. Jacksonville's 39 first-half plays from scrimmage produced 342 yards.
Indianapolis, on the other hand, ran 24 plays and gained just 72 first-half yards.
The Jaguars took the opening kickoff and drove 75 yards in 12 plays, scoring on Chris Ivory's 1-yard run in a drive that included a 24-yard pass from Bortles to wide receiver Marqise Lee to the Colts' 13.
Jacksonville increased its lead to 14-0 with 5:01 left in the first quarter on Bortles' 5-yard touchdown pass to tight end Marcedes Lewis in the back right corner of the end zone. A 52-yard pass from Bortles to wide receiver Keelan Cole moved the ball to the Colts' 18.
Josh Lambo's 42-yard field goal with 7:38 remaining in the second quarter gave Jacksonville a 17-0 advantage after a 12-play, 67-yard drive.
With 1:56 left in the first half, Lambo's 33-yard field goal capped an eight-play, 66-yard drive and gave the Jaguars a 20-0 advantage through 30 minutes. Bortles had completions of 50 and 15 yards during that drive, moving the ball to the Indianapolis 14.
In the first half, Jacksonville sacked Colts quarterback Jacoby Brissett three times and limited him to 5-of-10 passing for 37 yards. Brissett finished 22 of 37 for 200 yards.
Jacksonville continued its domination in the third quarter, increasing its lead to 27-0 on running back T.J. Yeldon's 58-yard touchdown run to cap a six-play, 91-yard drive.
Through three quarters, the Jaguars had 467 yards while Indianapolis had 147.
Bortles was 17 of 24 for 317 yards and a touchdown after three quarters while Brissett was 10 of 19 for 106 yards and was sacked six times.
NOTES: The Colts lost four starters to injury during the first three quarters: CB Rashaan Melvin (concussion), LB John Simon (stinger), FS Malik Hooker (knee) and C Ryan Kelly (hamstring). ... The Jaguars lost LT Cam Robinson (ankle) with 14:16 left in the first quarter. ... Jaguars RB Leonard Fournette was inactive because of an ankle injury. ... The Jaguars entered ranked eighth in scoring at 26.0 points a game. ... The Colts came in averaging 19.8 points a game, ranked 20th. ... Indianapolis leads the series 22-11, including 12-5 in Indianapolis and 10-6 in Jacksonville.