Blaine Gabbert threw for 118 yards with a score for the Jaguars (3-6), who won on the road for the first time in five games this season.
The Colts (0-10), meanwhile, have been unable to win anywhere. The are 0-5 at home and 0-5 on the road heading into their bye week. Indianapolis is winless after 10 games for the first time since the 1997 team also lost its first 10 on the way to a 3-13 record.
That was pre-Peyton Manning. With the four-time MVP and Super Bowl champion sidelined by a neck injury, the Colts hardly resemble an NFL team.
Curtis Painter was lifted in the fourth quarter after throwing his second interception of the game and Dan Orlovsky turned the ball over on his second throw, leading to Jacksonville's game-sealing touchdown.
The Colts totaled just 212 yards of offense. Painter completed 13-of-19 passes for 94 yards and Orlovsky finished 7-of-10 for 67.
Jacksonville snapped a 3-3 tie and reached the end zone first with an 86-yard march that ate up more than 9 1/2 minutes of the third quarter. A 17-yard pass from Gabbert to Deji Karim converted 3rd-and-9 early in the series and a penalty against Indianapolis' Tyler Brayton negated a third-down sack that would have forced a punt.
Instead, the Jaguars were given a fresh set of downs and Gabbert took advantage by hitting Jarrett Dillard with an 11-yard pass for the score to make it 10-3 with just 1:49 left in the third.
The Jaguars appeared to come up with a turnover on the next series when William Middleton picked off Painter. However, during the timeout on the change of possession, the Colts challenged that Jacksonville had 12 men on the field and the correct reversal allowed Indianapolis to keep the ball. But not for long, as Painter was intercepted three plays later by Paul Posluszny at the Jacksonville 21.
Indianapolis got the ball back at its own 13 with just under six minutes remaining and Orlovsky under center in place of Painter. It didn't help.
Orlovsky's arm was hit on his second pass attempt and the ball fluttered into the waiting arms of Jacksonville lineman Tyson Alualu. The play was ruled a fumble, setting up Jones-Drew's three-yard touchdown run to seal the contest.
Jones-Drew carried 25 times and added three catches for 23 yards. Gabbert completed 14-of-21 passes with an interception and hit nine different receivers.
The game's first two possessions ended in interceptions. Painter was picked off by Drew Coleman, giving the Jaguars a first down at the Indianapolis 18, but Jerraud Powers returned the favor with an interception of Gabbert inside the 10.
After a series of punts, Josh Scobee connected from 44 yards away to put the Jaguars on the board late in the first quarter. The Colts responded in the first minute of the second period with a 42-yard kick from Adam Vinatieri on the ensuing series.
The Jaguars had a chance to move in front just before the intermission, as a 19-yard pass from Gabbert to Dillard set up Scobee for a 45-yard try, but he missed wide right and the teams went to the break knotted at 3-3.
Donald Brown led the Colts with 53 yards on 14 carries and caught four passes for 12 yards...The Jaguars managed only 251 yards of offense...Jacksonville cornerback Rashean Mathis left the contest in the second quarter with an apparent knee injury...The Jaguars improved to 8-9 after a bye.