The Panthers (4-1) improved to 19-0 all-time against the MAC, including 2-0 this season. Pittsburgh opened the year with a 27-14 victory over Ohio.
Toledo (3-2) opened the scoring on Brian Jones' 44-yard touchdown pass to Carl Ford less than two minutes into the second quarter, but the Panthers erupted for three touchdowns in just over 10 minutes to open a 21-6 halftime lead.
Rutherford, who completed 18 of 27 passes and also ran for a score, gave Pittsburgh the lead for good with an 18-yard touchdown pass to Lamar Slade with 10:21 left in the half.
After Raymond Kirkley scored on a one-yard run, Rutherford tossed the first of his two TD passes to freshman Larry Fitzgerald, a seven-yarder with just 13 seconds left before intermission.
Pittsburgh, which has won 10 of its last 11 games, made it 27-6 on Rutherford's eight-yard run with 2:37 remaining in the third quarter.
Fitgerald hauled in a 26-yard touchdown in the fourth quarter and finished with six receptions for a season-high 121 yards.
Forced to play catchup, Toledo's Brian Jones completed 31 of 45 passes for 306 yards with two touchdowns and two interceptions. The Rockets were held to 104 yards rushing.