Manuel went 17-of-24 through the air for 193 yards as the Bills (5-9) snapped a two-game losing streak.
Robert Woods paced Buffalo's receiving corps with 82 yards and a TD on five catches.
Frank Summers added a scoring grab and Fred Jackson ran for 80 yards on 17 carries for the Bills.
The Jaguars (4-10) had their three-game winning streak snapped as Chad Henne was intercepted twice and held to 237 passing yards on 21-of-36 efficiency.
He completed scoring passes to Marcedes Lewis and Ace Sanders.