Jacksonville and Cleveland both go into the game with 3-6 records, but the Browns lost to St. Louis 13-12 last week while the Jaguars were beating the Colts.
The Jaguars hope the victory in the first game of the second half of the season will give them some momentum.
This is the fourth year in a row the Jaguars have played the Browns and the third time in four years they've played at Cleveland.
They lost at Cleveland in 2008 and 2009, but they beat the Browns 24-20 in Jacksonville last season.
"It's nice to get a win in the division on the road to start the second half of the season," coach Jack Del Rio said after his team topped the Colts.
The defense spearheaded the effort, holding Indianapolis to 212 yards of offense while collecting five sacks and three turnovers.
Defensive end Jeremy Mincey said, "I think we've got what it takes to be the best (defense in the league). We've got to prove it. We can talk about it all day, but we've just got to continue to go out there and prove it."
Del Rio said, "The defense was strong, in particular Jeremy Mincey was a force out there again today for us. We got more sacks than we allowed. We won the turnover battle. You win the turnover battle and you win the hitting battle and you have those things and take care of the football, then you go home with a victory. So we're happy to have accomplished that today."
The Jaguars would have gotten a shutout if not for a facemask penalty on Derek Cox that cost them 15 yards and put Adam Vinatieri in range for a 42-yard field goal.
Of the penalty, Cox said, "It was accidental. An aggressive penalty, trying to make a play."