The Cork rider led home his LayLaw Racing Yamaha team-mate Ian Lougher in a repeat of last year’s result.
Ulster’s Michael Dunlop, fastest in qualifying on his 250cc Honda, was an early retirement at the Railway, with Magherafelt man Paul Jordan also ruled out on the opening lap on the Faraldo Racing 450GP Yamaha, retiring at Selborne Drive.
Browne celebrated his maiden triumph around the Mountain Course last August and followed up in style for his second MGP success.
Sporting a replica Eddie Laycock helmet in tribute to the two-time TT winner who expertly prepares the LayLaw Racing TZ250 Yamaha machines, Browne seized the race by the scruff of the neck and was almost nine second ahead of Lougher at Ballaugh Bridge on the first lap.
His opening speed of 116.98mph was the fastest in the race, which was cut in-running from three laps to two with low cloud rolling in over the Mountain section.
Browne had a comfortable advantage of 11 seconds over Lougher after the first lap, which he extended to 27 seconds by Ramsey on lap two.
In total control, he brought the Yamaha home safely over the Mountain for the final time to secure a popular victory for Gerry Lawlor’s team by half-a-minute.
Third went to Manx rider Dan Sayle on the Baz Gas Honda with Banbridge man Shaun Anderson in fourth on his Kramer.
Northern Ireland’s Adam McLean, also riding for the LayLaw Racing team, finished fifth despite incurring a one-minute time penalty for failing to make his compulsory pit-stop after the first lap.
Earlier, Victor Lopez made history when he became the first Spanish rider to win at the Manx GP as he triumphed in the Junior race.
The Team ILR Paton rider was 14.8s up on Italy’s Andrea Majola, also riding a Paton, with fellow Italian Maurizio Bottalico in third on a Paton-dominated podium.
Lopez set a new lap record for the class at 117.645mph.
On Monday, the RST Classic Superbike and Junior MGP races bring the festival to a close.