But her revival began in earnest last year with another charge to the Wimbledon semi-finals and then a venture to the last eight at the US Open.
Williams is into her first final in Melbourne since 2003, when she also fell to Serena.
Vandeweghe had taken out titleholder and world No.1 Angelique Kerber, French Open champion Garbine Muguruza, former Wimbledon finalist Eugenie Bouchard and 2015 US Open runner-up Roberta Vinci during her march to the semi-finals.
The big-hitting world No.35 made another lightning start on Thursday, breaking Williams in the opening game of the match.
But contesting her 21st grand slam semi-final compared to Vandeweghe's first, Williams struck straight back as her less-experienced foe double-faulted on break point.
Games then went with serve until the tiebreaker, which Vandeweghe claimed to take a one-set lead.
It was the first set Williams had dropped all tournament - and she was quick to hit back.
Vandeweghe bounced her racquet into the court after dropping serve to love in the third game of the second set and was fortunate to escape a warning for belting a ball angrily into the crowd after being broken again to fall behind 4-1.
The big lead was enough as Williams wrapped up the second set with her eighth and ninth aces of the match.
Williams rode the momentum to another break in the opening game of the deciding set and there was no way back for Vandeweghe as the former world No.1 clinched victory on her fourth match point.
At 36 years and 226 days, she becomes the oldest woman in the 49-year open era to reach the final.
- AAP