Ligety's career-best result in downhill lifted him to third in the overall standings. His previous best in downhill was fourth, in 2007 at Lenzerheide where the steep, twisting course suits his technical skills.
"This is a hill I know I have a good chance on," said Ligety, the world champion in super-G. "I also don't count on this carrying through to other races on the World Cup downhill tour."
Aksel Lund Svindal of Norway retook the lead in the overall World Cup standings on Wednesday by placing fifth.
Svindal earned 45 points to move 41 ahead of two-time defending overall champion Marcel Hirscher of Austria, who skips downhills.
"If I had to put money on someone I have no idea who it would be," said Svindal, who will race against Hirscher in a super-G on Thursday.
Mayer earned his first career World Cup win in 1 minute, 29.99 seconds, 0.11 faster than Christof Innerhofer of Italy and Ted Ligety of the United States, who tied for second. Svindal was 0.20 seconds behind Mayer.
Mayer and Innerhofer finished 1-2 in the downhill at the Sochi Olympics.
"It's very important," Mayer said of his win. "It was a target for me to win a World Cup race this year. It's perfect."
Svindal, a two-time overall champion, already clinched his second straight season-long downhill title before the World Cup Finals.
"I used to be 1-2-3 every race, and now I'm 4-5-6," said the Norwegian, who has finished just off the podium since the Olympics. "But Marcel is too."
Svindal is scheduled to start the giant slalom on Saturday, but skip Sunday's season-ending slalom which is typically Hirscher's best event.
Bode Miller of the United States seemed poised for victory on Wednesday until going wide near the end of his run. He placed eighth, 0.62 behind Mayer.
Several racers found trouble on the hard, bumpy snow despite the clear, sunny conditions. Austrian Georg Streitberger twisted in the air while crashing when more than a half-second ahead of Mayer midway down.
The final women's downhill of the season was to start less than an hour later down the same 2.3-kilometer (1.4-mile) Silvano Beltrametti course.