Casey closed with a 4-under 68 to hold off a strong charge by Ross Fisher, who had a tournament-best 64.
It was not an easy putt, but no putt to win a title ever is, said Casey, who finished on 17-under 271.
It was the second victory at Wentworth for Casey, who captured the World Match Play Championship in 2006. And it followed victories earlier this year in the Abu Dhabi Championship and the Shell Houston Open, the latter his first victory in the United States.
Casey now trails only Tiger Woods and Phil Mickelson after starting the year at No. 41 in the world. He is the highest-ranked British player since Colin Montgomerie was at No. 3 at the start of the decade.
The Englishman also joined an impressive list of champions at Europes flagship event, which includes Montgomerie, Nick Faldo, Seve Ballesteros and Tony Jacklin.
This feels great, Casey said. All the great names are on this trophy, and I wanted to be there as well.
Soren Kjeldsen, who played in the final group with Casey, shot a 69 to finish alone in third. Rory McIlroy, whose 65 on Saturday put him in the mix, faded quickly with a 71 and had to settle for fifth.
Gonzalo Fernandez-Castano of Spain birdied the last hole for a 68 to tie for 11th, which should be enough for him to move into the top 50 in the world ranking and qualify for the U.S. Open for the first time, and the British Open for the second time.
Ben Curtis, one of the few Americans who has taken joint membership in Europe for the Race to Dubai, tied for sixth with a birdie-birdie-eagle-eagle finish (67), the last two holes being par 5s on the West Course at Wentworth.
Defending champion Miguel Angel Jimenez was never in contention, although he managed to get his name in the European Tour record books with a double eagle on the par-5 fourth hole when he knocked in his second shot from 206 yards with a 6-iron. He still shot 76.