The Jets quarterback's struggles continued in the first quarter as Preston Brown and Aaron Williams also picked off Smith passes, leaving him with three interceptions inside the first 15 minutes.
As a result, Michael Vick came off the bench at the start of the second quarter, quickly setting up Chris Ivory to get a touchdown back for the hosts.
While Lee Smith and Frank Summers also picked up first-half touchdowns for the Bills, a second Ivory effort ensured that the Jets were still in contention at half time.
The Jets managed to slow their AFC East rivals down in the third quarter, restricting them to two Dan Carpenter field goals.
However, Vick threw the home side's fourth interception of the game in the fourth quarter, allowing Orton back onto the field to pick out Scott Chandler, who just kept himself in bounds at the back of the endzone.
Orton piled more misery on the Jets when he found rookie wide receiver Sammy Watkins with a 61-yard pass for the Bills' fifth touchdown of the game on their next drive, opening up a 26-point lead for Buffalo.
Running back Bilal Powell got the deficit down to 20 after a three-yard run, but Vick could not make the two-point conversion.
The win keeps the Bills second in the AFC East, two wins behind the Patriots, while the Jets sit bottom in the division.