Willett, who tied sixth at The Open last week, shot a five-under par 65 to finish 17 under overall in Switzerland.
After sharing the lead with fellow Yorkshireman Fitzpatrick, 20, going into the final day, Willett, 27, managed a bogey-free final round.
In all-English top three, Tyrrell Hatton came third, finishing 15 under.
Hatton, from Buckinghamshire, carded a 62, the best round of the day at the picturesque Crans-sur-Sierre course, high up in the Swiss Alps.
His fifth top-six finish in 10 months, a run which started at Crans in the same event last September, when he finished joint third, lifts him 13 places to 102nd in the Official World Golf Rankings.
Willett, now the second-highest world-ranked Englishman, having climbed eight places to 24th, said: "I kept very calm all day. I just waited for the right things to happen to get on a run. I knew I couldn't let up as Matt was snapping at my heels. He played some great golf and really kept the pressure on, so I'm delighted to get the job done."
Spaniard Sergio Garcia was sixth after a final day 64, while England's Lee Westwood tied for 37th on three under, despite a 10 at the par-five 14th.
A week on from qualifying for his first Open at the age of 33, after 15 failed attempts, County Durham's Robert Dinwiddie, from Barnard Castle, enjoyed his second Top 10 finish in six weeks.
Danny Willett won his third European Tour title with Sunday's one-shot victory over fellow Englishman Matt Fitzpatrick at the European Masters.