It was Williams's fourth title triumph in Rome in 14 years, her 70th career title in all and her first since winning in Cincinnati nine months ago.
The 34-year-old great has looked more vulnerable of late, losing in the semi-finals at last year's U.S. Open and final at the Australian Open and Indian Wells this season.
Yet even though this was her first claycourt appearance of the season, it was enough to confirm she is in fine shape for Roland Garros, with plenty of room also for improvement.
For Keys, it was major breakthrough to reach only her third final and the youngster gave her opponent enough trouble for Williams to tell her afterwards: "I'm so proud of you. You can get to world number one."
Keys broke Williams's serve in the opening game and, able to match the world number one for power, she pushed the top seed into a tiebreak in the first set before succumbing.
Even though Williams looked a little rusty at times and was not quite at her best, she still took control in the second set to wrap up victory after one hour and 24 minutes.
(Reporting by Ian Chadband; Editing by Toby Davis)
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