Nadal, the world number four and second seed, produced an erratic performance on the clay in the Catalan capital and the big-hitting Fognini punished the Spaniard's errors to scupper Nadal's bid for a ninth Barcelona title.
Backed by a fiercely partisan crowd, Nadal saved three match points in the tiebreak before sending a forehand long on the fourth to hand Fognini victory.
After his 2014 season was wrecked by illness and injury, Nadal is looking to rediscover his dominance on the red dust before he makes a bid for a record-extending 10th French Open crown starting at the end of next month.
The Majorca native lost to world number one Novak Djokovic in the semi-finals of last week's Monte Carlo Masters and many are tipping the Serb to end his great rival's stranglehold at Roland Garros.
Despite his reverse to Djokovic in the principality, Nadal said he had played his best tennis of the year but admitted Thursday's reverse was "a blow" and that his misfiring forehand had been the key.
"I played badly and I couldn't play how I wanted," Nadal told a news conference.
"There is no other alternative, accept it or die, and I accept it because I want to give myself a chance in the future," added the 28-year-old, who is next due to play at the Madrid Masters at the start of May.
Fognini, who beat Nadal on clay in the semi-finals in Rio de Janeiro in February, his only win in five previous meetings, said he had needed to draw deeply on his mental strength to see out the match.
"Unless you play at your highest level against Rafa for the whole match you are not going to get the better of him," Fognini told Spanish television.
"Beating a player who is the greatest in history on this surface is worth double," he added.
On the other side of the draw, champion and top seed Kei Nishikori of Japan eased past Colombian Santiago Giraldo 6-2 6-1 and will play Spaniard Roberto Bautista for a place in Saturday's semi-finals.
(Writing by Iain Rogers in Madrid, editing by Justin Palmer and Toby Davis)
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