Orton, a nine-year NFL veteran, signed a one-year contract as the Bills finally addressed their lengthy search for an established veteran to play behind second-year starter EJ Manuel.
Orton spent the past two seasons in Dallas before being cut by the Cowboys in mid-July after he skipped the team's offseason workouts amid reports that he was considering retirement.
The Bills targeted a veteran after entering last season with two untested players: Tuel, an undrafted rookie, and journeyman Thad Lewis.
Lewis was cut on Tuesday and Tuel became the odd-man out in being among 10 players cut by the Bills to establish their 53-man roster.
That leaves Manuel and Orton as Buffalo's only two quarterbacks in preparing to open the season at Chicago on Sept. 7.
It's the latest switch of quarterbacks in Buffalo. Fifth-year player Jordan Palmer was signed on Tuesday and then cut on Friday, a day after throwing three interceptions in a preseason-ending 23-0 loss to Detroit.
The Bills also carrying two punters after signing Colton Schmidt, who spent the past two preseasons with San Francisco before being cut each time by the 49ers. He joins Jordan Gay, who was signed earlier this week.
Receiver T.J. Graham, a third-round pick in the 2012 draft, and veteran offensive lineman Doug Legursky were among the notable players released Saturday.
Graham, who had 54 catches for 683 yards and three touchdowns in 31 games, was unable to get a spot in a group of receivers that included the offseason additions of first-round draft pick Sammy Watkins and veteran Mike Williams.
Also cut were safeties Deon Broomfield and Kenny Ladler; linebacker Jimmy Gaines; receiver Caleb Holley; defensive ends Ikponmwosa Igbinosun and Bryan Johnson; and guard Antoine McLain.
The Bills are actually carrying 54 players, including linebacker Nigel Bradham, who won't count against the roster in Week 1. Bradham was suspended for one game by the NFL for violating the league's substance abuse policy.
The Bills had Orton on their radar for more than a month, but had their previous offers rebuffed.
He was Chicago's fourth-round pick in 2005, and also played in Denver and Kansas City. He has a 35-35 record and gone 1,326 of 2,265 for 15,019 yards with 83 touchdowns and 59 interceptions.
He went 10-5 as a rookie in leading the Bears to the playoffs while filling in for injured starter Rex Grossman. Orton did not play the following season after Grossman reclaimed the starting job.
Orton eventually spent two-plus seasons in Denver before losing the starting job to Tim Tebow.
He spent the past two seasons backing up Tony Romo in Dallas, where Orton went 42 of 61 for 479 yards with two touchdowns and two interceptions in four games. That included a start in last year's season-ending 24-22 loss to Philadelphia that was sealed by Orton throwing a late interception.
Orton could be in line for playing time in Buffalo.
Manuel was both injury-prone and inconsistent as a rookie last year. The first-round pick finished 4-6 and missed time because of three separate knee injuries.
Though Manuel has remained healthy this offseason, the Bills' offense has sputtered. The Manuel-led starters combined to score four field goals and two touchdowns in five preseason games.
AP NFL website: www.pro32.ap.org and www.twitter.com/AP-NFL