Williams' title defence came six years after Kim Clijsters completed her double.
"I'm so glad to be done here," said Williams, who got a scare in a tight 53-minute opening set but easily won the second set. "I was glad to come here but it was tough.
"I flew from Wimbledon and had to get adjusted to the conditions and beat the jet-lag. I was glad to play and it's great to win.
"But now I want to stay in the States for a while and prepare for the London Olympics."
Williams defeated Vandeweghe in 90 minutes, hammering 21 winners, nine aces and getting four breaks of serve.
Vandeweghe, ranked 120 but set for a rise into the top 75, was bidding for history in hopes of becoming the second lucky loser from qualifying rounds to win a WTA Tour title. The Californian got into the field after another player withdrew before the start.
"It was really exciting to be in the final, hopefully this was a good omen for the rest of the summer," she said. "Hardcourt is definitely my favourite surface. I'm happy to be out there playing."
The performance earns the Californian a direct entry into the US Open.
Williams has two trophies in as many weeks after winning Wimbledon last weekend, then flying to northern California to shift onto the hardcourts. The world number four now owns 43 career titles, the same number as her sister Venus.
Williams also has four wins in 2012, putting her joint leader in that category alongside world number one Victoria Azarenka.
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