Watson crashed an outstanding 122 from just 111 balls in his first international outing since he injured his calf while batting during the Boxing Day Test in Melbourne more than a month ago.
Watson, 31, is attempting to rebuild his standing as a premier opener in Australia's line-up in time for the anticipated four-Test series against India in the sub-continent.
It was Watson's first century in any format for Australia in almost two years since he plundered an unbeaten 185 against struggling unit Bangladesh in April 2011.
Watson was out in the 34th over as the Aussies plundered on to a formidable 7-329 in 50 overs and genuine prospects of a third straight win to seal the five-game series at 3-nil already.
After losing Watson and then number three Phil Hughes in the 46th over, the home side lost late wickets in trade-off for handy runs and an imposing tally for the Windies to chase under lights for a first-ever time in the national capital.
Hughes, 24, continued his astonishing batting rebirth with another big score of 86 from 93 balls with 10 fours and a six.
Perth century-maker last Sunday George Bailey chipped in with a handy 44 before he lost his wicket in the 49th over.
Captain Michael Clarke was out for 15 and big-hitter Glenn Maxwell for just four deep in the home side's innings as Australia rampaged in the hunt for late runs.
Aaron Finch was the early casualty for 38 Clarke won the toss and batted.
Watson cracked 12 fours and two big sixes in his stunning re-start to international ranks.
It was Watson's sixth limited-overs century in 154 one-day matches.
Watson replaced Usman Khawaja at the top of the Aussie line-up with Finch who was given another chance after poor scores of 16, 4, 10 and 11 in his limited-over outings so far this summer.
Windies skipper Darren Sammy (2-49) and off-spinner Sunil Narine (2-55) were the better Windies bowlers as the Aussies hammered their way to the edge of another commanding victory.