Miami was in position to tie or win when reaching the North Carolina 16-yard line in the final minute, but linebacker Cedric Gray intercepted a tipped pass with 6 seconds left.
"It's like a roller-coaster. When you hop on it, you feel like you're in good shape and then you go back down and come back (up)," North Carolina coach Mack Brown said. "One thing this team hasn't done this year is won a tough game at the end."
Ty Chandler ran for two touchdowns for the Tar Heels (4-3, 3-3 Atlantic Coast Conference) in a matchup of two teams that began the season in the Top 15, but are trying to gain traction midway through the season.
The Hurricanes (2-4, 0-2) are 2-4 for the first time since 1997 when they were on NCAA probation and stuck with scholarship limitations.
"I'm proud of the way these guys fight. I know that (another win) is coming," Miami coach Manny Diaz said. "There's a really good team in that locker room. We don't have a good record."
Howell was 17 for 26 for 154 yards in the air with an interception while running for 98 yards on 17 carries. Chandler gained 104 yards on the ground on 18 attempts.
Howell's touchdown runs covered 30 and 11 yards, both times pinballing off Miami defenders.
"A couple of times he just ran through arms and twisted and went in to score," Brown said.
Miami nearly erased an 18-point deficit, pulling within 38-34 before stalling in North Carolina territory early in the fourth quarter. Then the Tar Heels drove 58 yards for a touchdown, aided by 30 yards on Miami penalties.
Freshman Jaylan Knighton ran for two Miami touchdowns, including a 4-yard run to cap a 97-yard drive with 3:08 remaining that was followed by a successful two-point conversion pass play.
The Hurricanes, after using all their timeouts, regained possession at the 2:46 mark and picked up 56 yards before the last interception.
"Those are the breaks that are tough to stomach for a team that is battling like ours," Diaz said.
Miami used Tyler Van Dyke, who made his third career start and first away from home, at quarterback just days after it was announced that D'Eriq King would be lost to season-ending shoulder surgery.
Van Dyke, who was 5 for 15 and picked off twice in the first half, finished 20 for 45 with 264 yards with a touchdown and three interceptions.
Miami: The Hurricanes don't seem equipped to overcome much adversity and they encountered more of it in their first true road game of the season. Miami lost team rushing and scoring leader Cam'Ron Harris to a lower-body injury on the first drive of the second half.
North Carolina: Downs has scored on a touchdown reception in every game this season, including the team's first TD on a 45-yard play Saturday. He has an eight-game TD streak dating to last season. He made 10 of his 11 receptions in the first half, ending up with 96 yards.
LET'S GO FOR IT
Van Dyke's numbers weren't overwhelming, but Diaz said his impact was huge.
"Everything that was thrown at him," Diaz said. "The way he fought back and led us at the end."
Van Dyke's fourth-quarter efforts were why Diaz was intent on aiming for a touchdown rather than a potential tying field goal on the last drive. Van Dyke threw for 104 yards in the fourth quarter.
"I'm putting our confidence in Tyler Van Dyke," Diaz said.
Miami is home against No. 22 North Carolina State on Saturday.
North Carolina has an open week before traveling to Notre Dame on Oct. 30.
North Carolina thwarts Miami in ACC showdown
Sam Howell accounts for 4 touchdowns as the Tar Heels hold off the Hurricanes 45-42.