The overall champion, who had already won the downhill title, won in 1 minute, 46.56 seconds on the Streicher course to beat second-place Marion Rolland of France by 0.92 seconds. Tina Maze of Slovenia came 1.22 back in third.
It was the American's 53rd career title and 12th win this season. Only Vreni Schneider of Switzerland won more races in one year — 14 in 1988-89.
"This definitely is my best season ever. It went well in all disciplines," Vonn said. "Twelve wins in one season, I can't believe it's true."
Vonn earned her 17th podium finish this season, which leaves her one short of the record shared by Hanni Wenzel of Liechtenstein in 1980 and Pernilla Wiberg of Sweden in 1997.
With a super-G and a giant slalom race left, the American standout is also within reach of the 2,000-point record for one single season held by Hermann Maier of Austria.
"I can't compare myself to Hermann," Vonn said. "He is a true legend of our sport. He has won so many races and has done so much for our sport, like Annemarie Moser-Proell has done on the women's side."
Vonn, who has 1,908 points, said that overtaking Maier's record is "going to be another fight ... I will try to get to these 2,000 points. It won't be easy on this (soft) snow. Hermann was a genius when he achieved it back in 2000."
Vonn put in a trademark downhill performance and charged throughout the race. Her advantage over then-leader Rolland grew at every intermediate time.
"It was no easy race," Vonn said. "The snow was weak and it was warm. I was afraid that the snow would not hold up but luckily it was OK. It was a really big day for me but tomorrow is another test."
The race took place in sunny conditions while mild temperatures and rain over the last couple days had softened the snow on the course, which will also be used for next year's world championships.
Until Vonn beat all other results, Rolland had been in the lead after a clean run. The French speed specialist had never been on a World Cup podium before.
"My coaches told me to be mean, to be more aggressive as usual," Rolland said. "I am very happy that it worked out so well. Today I was angry in a way people wanted me to be angry."
Tina Maze of Slovenia earned her 10th podium finish of the season and now has a top-three result in all five disciplines but is still lacking a win.
"It's a great season for me with a lot of podiums," the world giant slalom champion said. "Unfortunately a win is missing until now, so something is still missing for total excitement."
World champion Elisabeth Goergl started fast and led Rolland at the first section but lost time as she skied off course and finished 1.92 off the lead in eighth.
Last year's overall champion, Maria Hoefl-Riesch, never looked comfortable during her run and struggled to keep the race line. The German came 2.55 back in 13th.
Julia Mancuso, who was second in Tuesday's training run, was fast again at the upper part but lost pace near the finish to take sixth, while teammate Alice McKennis was the third American in the top seven.
The World Cup finals continue with both men's and women's super-G races on Thursday.