Roethlisberger finished 17 of 24 for 169 yards passing, including a 6-yard touchdown pass to Antonio Brown to cap a 98-yard drive in the final seconds of the first half. Brown also scored on a 39-yard TD pass from Byron Leftwich a minute into the second half in helping the Steelers improve to 2-1.
"I just started calling my own plays," said Roethlisberger, who at one point angrily gestured at his sideline after the Steelers were penalized for an illegal substitution early in their 98-yard march. "We went no-huddle and up-tempo, and we were throwing the ball."
Brown finished with seven catches for 108 yards and was impressed with how the Steelers responded from a slow start.
"It was all Ben," Brown said. "It's all about how you respond to adversity. I think we did a good job rallying back toward the end of the half."
Isaac Redman also scored on a 2-yard run, Leftwich threw two touchdown passes, including a 10-yarder to Derrick Williams, and running back Chris Rainey capped the rout with a 41-yard touchdown run with 2:44 left.
The Steelers defense also contributed, forcing three turnovers -- a forced fumble and two interceptions -- all of which led directly to touchdowns.
The Bills dropped to 0-3 this preseason while continuing a trend of familiar struggles on both offense and defense. And that's not what coach Chan Gailey was looking for this week in expressing a desire to see more consistency from his starters.
"The one thing that we have not had all preseason camp is learning how to handle our composure," Gailey said at halftime, referring specifically to the defense giving up the touchdown drive at the end of the second quarter. "They kind of got rattled and lost their composure a little bit. And that is what we have to work on."
The Ryan Fitzpatrick-led offense managed just 131 yards and seven first downs in playing the entire first half. It was limited to scoring just one touchdown - Fred Jackson's 1-yard plunge - despite five of seven possessions inside Steelers territory.
The Bills defense was sharp for much of the first half, before wilting on the final drive in allowing the Steelers to go ahead 14-7 with 13 seconds left.
Fitzpatrick finished 7 of 18 for 89 yards, while backup Vince Young struggled in his bid to clinch the No. 2 job. Young went 12 for 26 for 103 yards passing and two interceptions.
On the bright side, Bills defensive end Mario Williams - who became the NFL's highest-paid defensive player after signing a six-year $100 million contract in March - was credited with his first two sacks of the preseason. Defensive tackles Kyle Williams and Marcell Dareus also had a solid game in plugging the middle while also flushing Roethlisberger out of the pocket.
The trouble was a failure to finish, in allowing the Steelers to score despite being backed up deep in their own end.
With starters expected to get very limited - if any - playing time in the Steelers' preseason finale against Carolina on Thursday, Roethlisberger showed he's ready for the regular season in finishing the first half.
In closing the half with a touchdown, the Steelers gained more yards (99 in total) than the 96 they had in their first six possessions.
And it was a drive that was going backward before Roethlisberger got fired up.
With the Steelers backed up at their own 2, they were penalized for an illegal substitution coming out of a timeout. After showing his displeasure by pointing to his own sideline, Roethlisberger responded two plays later. Facing third-and-9, Roethlisberger hit running back Jonathan Dwyer with a perfectly placed 33-yard pass up the left sideline.
He eventually hit 8 of 9 attempts for 95 yards on the drive, and against a Bills defense that had kept him in check for much of the first half.
Roethlisberger did it with an offense that's missing two key starters, running back Rashard Mendenhall (right knee) and receiver Mike Wallace (contract holdout). And it was a unit that lost rookie first-round draft pick, right guard David DeCastro, who did not return after hurting his right knee on the second possession.
It didn't take long for the Steelers to build their lead in the third quarter.
Taking over for Fitzpatrick, Young had his first attempted intercepted, when he floated a pass toward the left sideline that was picked off by Troy Polamalu. Leftwich then hit Brown with perfect pass deep over the middle on the next play from scrimmage.
Leftwich finished hitting 5 of 8 for 105, and his TD to Williams came shortly after Robert Golden intercepted Young early into the fourth quarter.
The Bills' only scoring drive came on their second possession, and set up by Fitzpatrick's 25-yard pass in hitting David Nelson on a crossing pattern over the middle.