The Yamaha rider took advantage of Marc Marquez's risky race strategy to claim maximum points in dramatic fashion, with the defending MotoGP champion paying the price for staying out in steady rain while his rivals changed bikes.
Championship leader Marquez elected to remain out on the Spanish circuit, but crashed with a couple of laps remaining, allowing Lorenzo - who had earlier switched bikes - to secure his maiden victory of the season.
Fellow Spaniard Aleix Espargaro and Englishman Cal Crutchlow finished second and third respectively, while Marquez was 13th.
Marquez's finish meant he claimed three points, while his team-mate Dani Pedrosa finished one place lower, having also spun off a lap earlier.
The results mean Marquez has extended his lead at the top of the standings by one point, and the reigning champion now holds a 75-point advantage with four races remaining.
His wait to equal Mick Doohan's record of 12 race wins in a season goes on and, after taking 11 of the first 12 races of the campaign, the Spaniard has now accrued just four points from the previous two meetings.
Ducati's Andrea Iannone, who had started the day third on the grid, spun off in spectacular fashion in the early stages but appeared to emerge unscathed.
There was some concern over Valentino Rossi, who crashed out heavily shortly after Iannone, and was carried away on a stretcher before being taken to hospital for precautionary scans.
As the rain began to fall, the leading pair of Marquez and Pedrosa took a gamble in choosing to remain on the track when the majority of the field pitted, and the risk failed to pay off as Lorenzo was able to cruise to victory over the final couple of laps.
Lorenzo's victory moves him within 12 points of the now third-placed Rossi in the standings, whose crash dropped him a point behind Pedrosa.