Merighetti flew down the course at Cortina d'Ampezzo in 1 minute, 33.17 seconds, beating second-place Vonn by 0.21 seconds.
Maria Hoefl-Riesch of Germany came in third a 1:33.57. Julia Mancuso of the United States finished sixth.
The win was the first for the Italian veteran and came on a day when blustery winds buffeted the skiers on their high-speed runs.
"The problem at the start was that the wind was swirling and I couldn't even see the first gate, "said Vonn. "There's not much you can do about it when it's so windy, so you just have to try to ski your best."
Vonn's second-place finish was enough to maintain her lead in the overall FIS World Cup standings by 244 points over Austria's Marlies Schild. She also leads the downhill standings by 127 points over Austrian Elisabeth Goergl.