Senden closed with a three-under 68 in the final round to secure his first PGA TOUR title, ending at 19-under-par 265 for a one-shot victory over J.P. Hayes.
'I've been at it for five years over here and it's just a great feeling,' said the Australian, who collected $720,000 for the win.
Alex Cejka and Heath Slocum finished tied for third place at minus-15 after rounds of 67 and 68, respectively, on the TPC at Deere Run.
Senden, 35, carded four birdies and one bogey in his final round and became the latest in a formidable list of players to earn their first PGA TOUR win at this event.
He joined a group that includes Scott Hoch (1980), Payne Stewart (1982), David Toms (1997) and last year's winner, 2005 Rookie of the Year Sean O'Hair.
Like O'Hair, Senden will accept an invitation to be the final player in the field next week at Royal Liverpool. He missed the cut in his only other British Open start in 2002.
'I'm excited,' Senden said. 'I was there in '02 at Muirfield, and it's just going to be another great experience.'
With all the pressure of playing for his first win resting on 35-year-old shoulders, Senden, the overnight leader, opened his final round with consecutive birdies at the first and second holes.
At the par-3 seventh, he knocked his tee shot within 4 1/2 feet and rolled in the birdie putt to reach 19 under. Senden led by four shots after eight holes, then three-putted for bogey at the par-4 ninth to drop to minus-18.
'I really battled through the whole day,' he said.
Playing in the group ahead of Senden, Hayes made a 16-foot birdie putt at the 14th to get to 17 under and within one shot. From 203 yards out at the par-5 17th, Hayes knocked his second shot within six feet but pushed his eagle putt.
He was tied for the lead at the time, but Senden would soon take care of that with a two-putt birdie of his own at 17.
For Hayes, who has made four cuts in just nine starts on the PGA TOUR this season, playing this event put him in a good mind set.
'I just feel real comfortable here,' he said. 'I don't know how many more times I'm going to get in (to the field) this year, so I have to take advantage when I do.'
Hayes' hope for a playoff was alive and well after Senden knocked his approach shot at the 18th into a greenside bunker -- 50 feet away from the hole. But it faded fast when Senden knocked the bunker shot within tap-in range to save par for the championship.
'The heart was going, and I just lobbed it out and let it go down there for the tap-in,' said Senden, who became the fifth Australian to win on tour this season.
Senden's other worldwide wins came at the 1996 Indonesian PGA Championship and at two European Challenge Tour events. He wasn't the only so-called 'no-name' on the leaderboard Sunday.
Michelle Wie withdrew on Friday because of heat exhaustion, and top-100 players were almost nowhere to be found.
Behind Cejka and Slocum, John Riegger shot a 64 to tie for fifth place with B.J. Staten (67) at 15 under.
World No. 62 Billy Mayfair was one shot further back with Kent Jones and Patrick Sheehan, while Jason Gore and 2004 British Open winner Todd Hamilton led a group of seven players who shared 10th place at minus-13.