Backup quarterback Grant Hedrick threw for 150 yards and ran for 115 more.
Hedrick, a junior who had only attempted 36 passes in his career, took over when starting quarterback Joe Southwick injured his right foot on the Broncos' first offensive play from scrimmage. He finished 18-of-21 passing.
He is also the first Bronco quarterback to rush for over 100 yards since Jared Zabranski rushed for 123 against Hawaii in 2004.
Boise State (5-2, 3-1 Mountain West) won its eighth straight game at home against Nevada.
Nevada (3-4, 2-2), which led at halftime against Boise State for the first time since 1997, lost its fifth straight on the road dating back to last season.
Boise State's defense, which yielded 246 yards of offense in the first half, held Nevada to 127 yards in the second half.
Trailing 17-7 at halftime, the Boise State offense also found its rhythm in the second half.
On their first possession of the second half, the Broncos drove 64 yards in eight plays, scoring on a 4-yard touchdown run by Ajayi. A missed extra point left Nevada with a 17-13 lead.
On Boise State's next possession, Ajayi raced 71 yards for a touchdown on the first play from scrimmage. With the extra point, Boise State took its first lead at 20-17 with 9:31 left in the third quarter.
Boise State added two more touchdowns to secure the victory.
Nevada receiver Brandon Wimberly led the Wolfpack with 11 catches for 121 yards. However, his streak of five straight games with a touchdown reception was snapped.