Guidugli tossed touchdown passes of 78, 49 and 48 yards to Jon Olinger and also hooked up with George Murray for a scoring strike of 26 yards.
Cincinnati (7-6, 6-2 C-USA) shared the Conference USA crown with Texas Christian, earning a piece of its first league championship since winning the Missouri Valley Conference title in 1964.
The Bearcats also secured Conference USA's fourth bowl berth and will play in either the New Orleans Bowl on Dec. 17 or the Hawaii Bowl on Dec. 25.
Cincinnati overcame a 2-5 start by winning five of its last six games.
The Bearcats defeated TCU, 36-29, in overtime in the season opener, but the Horned Frogs will represent Conference USA in the Liberty Bowl.
Guidugli completed 15 of 28 passes for 323 yards. He finished the season with a school-record 3,319 passing yards, breaking the previous mark of 3,272 set by Greg Cook.
Demarco McCleskey rushed for 161 yards on 30 carries for the Bearcats. Olinger caught just four passes for 194 yards, an average of 48.5 yards per catch.
Cincinnati also returned two interceptions for a touchdowns, a 12-yard return by Blue Adams in the first quarter and a 30-yarder by Zach Norton that completed the scoring with just over three minutes remaining.
On three occasions, East Carolina (4-8, 4-4) closed within two points after trailing 14-6 at intermission. Each time, Guidugli answered with a touchdown pass. His last scoring toss to Murray gave Cincinnati a 35-26 lead with 9:35 to play.
Paul Troth was 20 of 42 for 285 yards for the Pirates. Chris Gilliam rushed for 158 yards and two touchdowns on 27 carries.