Watson, involved throughout in a trip that saw Australia arrive in Britain in May before their early Champions Trophy exit was followed by a 3-0 Ashes series loss, made 143 in a total of 298 all out.
Together with Australia captain Michael Clarke (75), he shared a fourth-wicket partnership of 163 on a ground where they'd both played for Hampshire after their side had slumped to 48 for three in this day/night clash.
However, no other batsman made more than opener Aaron Finch's 26 as Australia fell short of a total in excess of 300 that seemed well within their grasp.
Durham all-rounder Ben Stokes led England's attack with five wickets for 61 runs -- the 22-year-old paceman's maiden five-wicket haul in 10 ODI matches.
England debutant Chris Jordan, in for injured fast bowler Steven Finn, took three for 47 after his first ball in international cricket was hit for four by Finch, whose last visit to this ground saw him score a Twenty20 world record 156 against England on August 29.
But Australia had more than enough runs as they enjoyed a win over England ahead of the return Ashes 'Down Under' starting in November.
England's reply got off to a disastrous start when Kevin Pietersen was run out for nought after being slow to respond to Michael Carberry's call.
Carberry, on his Hampshire home ground, pressed on to 30 before he was lbw to left-arm seamer James Faulkner, who took three for 38.
And it wasn't long before 50 for two became 68 for four.
Joe Root (13) played on to Mitchell Johnson before Luke Wright, in for the injured Jonathan Trott, was run out for a duck following George Bailey's direct hit from cover.
Stand-in captain Eoin Morgan, leading a side missing five rested Ashes-winners including regular skipper Alastair Cook, fell for 30 when he was stumped by wicketkeeper Matthew Wade off left-arm spinner Adam Voges.
England's hopes now rested with Ravi Bopara and Jos Buttler, whose 65 not out turned the tide in a series-levelling three-wicket win in Cardiff on Saturday.
Buttler scored at better than a run-a-ball but Faulkner, cleverly changing to around the wicket, bowled him for 42 to end a stand of 92 with Bopara.
And when Bopara, who made 66, followed when well caught at extra-cover by Voges off Johnson to give the left-arm fast bowler his 200th ODI wicket, England were effectively beaten at 197 for seven.
Pakistan-born leg-spinner Fawad Ahmed wrapped up the match when he bowled last man Boyd Rankin with two overs left.
After Clarke won the toss, Jordan had Phil Hughes (two), opening in place of the injured Shaun Marsh, top-edging a pull to Carberry at midwicket.
Australia, on a ground where New Zealand's Martin Guptill struck 189 not out against England in an ODI in June, saw 48 for one become 48 for three when Stokes took two wickets in two balls after a 30-minute rain break.
Finch was caught by Morgan at point and next ball Matthew Wade gloved an intended hook to Buttler, the first of five dismissals for the wicketkeeper.
Clarke, passed fit after fears he'd suffered a recurrence of his long-standing back injury, survived the hat-trick and produced another fine innings to follow his hundred in Australia's 88-run victory in the second ODI in Manchester.
He was eventually out when he sliced a pull off Jordan to Pietersen at mid-off to end a 76-ball knock including 10 fours and a six.
Watson's dominant 107-ball innings, featuring 12 fours and six sixes, finished when he was caught behind off Stokes.