Ruud had to dig deep in the deciding set on Saturday, breaking Sousa when the Portuguese was serving for the title at 5-4, before going on to win 7-6 (7-3) 4-6 7-6 (7-1).
The world No.9 has now won six of his last seven ATP 250 events on clay, and is the first player since Stan Wawrinka (2016 and 2017) to win more than one Geneva Open title.
Ruud served five aces in the first set on his way to edging a tie-break, but a determined Sousa was able to level in a second set in which he won eight of 11 second-service points.
It looked like Sousa would cause an upset against the tournament's second seed when serving for the match, only for Ruud to break back and use that momentum to take the win.
The Norwegian made the semi-finals in Rome last week and maintained his momentum ahead of the French Open by lifting the trophy in Switzerland.
"It was one of the craziest matches that I have ever played," he said in his on-court interview. "It was a lot of up and down. Sousa was close to winning and then suddenly everything turns around and this is tennis."
Also on Saturday Briton Cameron Norrie won his second ATP title of the year when he beat Alex Molcan of Slovakia 6-3 6-7 (3-7) 6-1 in the Lyon Open final.
Norrie missed two match points on Molcan's serve in the second set, but took his third chance to end the final after 2 1/2 hours.
"It is my first title on the clay so it means a lot to me," No. 11-ranked Norrie said.
Molcan, ranked No. 47, was going for his first title.
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