They first loss track of Travis Benjamin, who made the Bills look silly all over the field. Then they lost two leads, their leading wide receiver and finally their starting rookie quarterback.
Buffalo's big night on prime-time national TV couldn't have gone much worse.
Unable to move on offense after quarterback EJ Manuel went out with a knee injury in the third quarter, the Bills dropped their sixth straight road game, 37-24 on Thursday night.
The Browns (3-2) rallied behind Brandon Weeden to move into sole possession of first place in the AFC North.
The Bills (2-3) led 10-0 in the first quarter before giving up 17 straight points, which included Benjamin's electrifying 79-yard punt return for a touchdown late in the first half.
C.J. Spiller scored on a 54-yard TD run early in the third quarter and Fred Jackson scored his second 1-yard TD run to give the Bills a 24-17 lead shortly after Manuel went down after taking a helmet to the knee while scrambling on a 14-yard gain.
Manuel tried to get loose and return, but couldn't and was done.
So, too, were the Bills.
"When you lose your quarterback and receiver, it's going to be tough but you have to deal with it," Jackson said. "It's the NFL. Injuries are going to happen."
Leading wide receiver Stevie Johnson sustained a back injury in the first half and didn't return. He missed much of spring practices with a back issue.
Bills coach Doug Marrone said Manuel has a sprained knee and assumes the first-round pick will undergo an MRI on Friday.
"I was hoping we could get him back, but they said it was a sprain and they shut him down," Marrone said. "He's a tough kid. He took a shot. He was trying to score a touchdown."
Manuel got hurt at the end of a 14-yard run when he was hammered near the sideline by Browns safety Tashaun Gipson. Manuel walked off the field and attempted to get his knee loose on the sideline by jogging and riding a stationary bike. But after having his knee examined, he went to the locker room with two trainers.
"I saw him working out and thought and we could get him back," Marrone said.
Rookie Jeff Tuel came in for Manuel but was ineffective, completing 8 of 20 passes for 80 yards. With the Bills down by six in the final two minutes, Tuel's pass was picked off by Browns safety T.J. Ward, whose 44-yard TD return clinched it for Cleveland.
"It was a misread on my part," Tuel said. "I didn't see the safety flying down."
Tuel was disappointed in his performance, but may need to shake it off quickly in the event Manuel is out for an extended period.
"It's the situation of any backup quarterback in the league," Tuel said. "You have to be ready to go in and perform at a high level."
Just before halftime, Benjamin broke several tackles, spun a few others on his dazzling return.
"We can't have that," Marrone said. "He's a good punt returner and he has a lot of speed. We knew that going in."
Weeden came off the bench after Brian Hoyer injured his knee and rallied the Browns, who have won three straight after an 0-2 start.
After spraining his right thumb in Week 2, Weeden watched as Hoyer, a lifelong Browns fan who began the season as Cleveland's No. 3 quarterback, led the team to two straight wins. Weeden got healthy enough to play but found himself demoted to a backup role, not what the first-round draft pick imagined after being named the starter in training camp.
He could have sulked or complained. Instead, he fought back.
"Whether I was the starter, eyes are still on you to see how you respond, to see how you react," he said. "I was upbeat the entire time and never let it bother me. Inside, it just kind of lit a fire."
Weeden threw a 37-yard touchdown pass to Josh Gordon in the third quarter as the Browns matched their best record after five games since 2001.
Hoyer sustained a potentially serious right knee injury on a scramble in the first quarter. With the Browns trailing 7-0, Hoyer took off on an 11-yard run and was sliding after picking up the first down when he was hit from the side by rookie linebacker Kiko Alonso.
Both of Hoyer's knees were bent awkwardly on the hit in front of Cleveland's bench, and several players and coaches yelled for a penalty to be called on Alonso. Hoyer stayed on the ground for several moments before he was assisted to a trainer's table.
Following the game, Hoyer left the stadium on crutches with his knee immobilized. Browns coach Rob Chudzinski said Hoyer has a sprained knee and will undergo an MRI on Friday. But the tone of Hoyer's teammates seemed to indicate that the 27-year-old, who was finally getting a chance to start in his fifth NFL season, might be sidelined for an extended period.
NOTES: Spiller and Jackson both missed practice this week. Spiller had 66 yards on eight carries, and Jackson had 53 yards on 17 with the two TDs. ... Bills S Jairus Byrd missed his fifth straight game with a foot injury. Byrd was ready to return after practicing, but the coaches decided to keep him out. ... Bills DE Mario Williams had two sacks, moving him into a tie for the league lead with 7½. ... Bills WR T.J. Graham sustained a neck injury in the fourth but returned.