"I don't think we gave ourselves a chance to make it a game," he said. "I thought after the last two weeks we were really making progress."
Jacksonville (2-10) sputtered on offense, gaining 236 yards, and faltered on defense by allowing the Bills to score on five straight possessions that produced 27 points bridging the second and third quarters. That put the game away.
"We felt like we were playing better and had been improving, bad record aside," said linebacker Paul Posluszny, who had an interception against his former team. "This would have been a great opportunity to beat an AFC opponent on the road, and we came up very, very short. We did not play well at all."
Quarterback Chad Henne scored on a 1-yard run, and also connected with Cecil Shorts III for a 5-yard touchdown a play after Bills backup punt returner Justin Rodgers' fumbled inside his 10 early in the fourth quarter.
Otherwise, the Jaguars had difficulty moving the ball. After going ahead 10-7 on Henne's 1-yard run in the second quarter, they managed just five first downs on their next four possessions, which ended with a lost fumble, a failed fourth-down conversion and two punts.
The Bills went ahead for good late in the second quarter when Ryan Fitzpatrick hit tight end Scott Chandler for an 11-yard touchdown.
"If we would have fought as hard as we could and played our best ball and lost, that's one thing," Posluszny said. "But that wasn't the case."
Fitzpatrick threw two touchdown passes and scored on a 1-yard run, Fred Jackson had 101 yards rushing and fellow running back C.J. Spiller capped the victory with a 44-yard touchdown run in the fourth quarter in helping Buffalo score more than 20 points for only the third time in eight games. Buffalo (5-7) also won for only the third time in nine games.
"We were facing two great running backs, and two very talented running backs," Posluszny said. "If we are not exact in what we do defensively, stuff like today happens with all the rushing yards given up."
Mario Williams had a sack, his sixth in four games and team-leading 9 1/2, in which he stripped the ball from Henne and recovered the fumble.
The loss spoiled Mularkey's first return to Buffalo since he abruptly resigned after two seasons as Bills coach in January 2006.
After going 33 of 59 for 615 yards and six TDs in his past two games, Henne struggled. He finished 18 of 41 for 208 yards and a game-ending interception that was picked off by safety Jairus Byrd.
"We did take a step back," Henne said. "We hurt ourselves with a lot of penalties, and didn't run the ball very well."
Already playing without running back Maurice Jones-Drew (foot), the Jaguars lost his backup Rashad Jennings, who sustained a concussion early in the second quarter.
Shorts scored on a 5-yard catch before leaving the game with a concussion in the fourth quarter.
NOTES: Fitzpatrick and Stevie Johnson have combined for 22 touchdowns, moving into a tie for fourth on the Bills list in joining Jim Kelly and Pete Metzelaars. ... Chandler's touchdown was his sixth of the season, matching the team's single-season record for tight ends shared by himself (2011), Metzelaars (1992) and Jay Riemersma (1998). ... The Jaguars squandered a chance to score 20 points in three straight games for the first time since a four-game streak in 2010.