The 28-year-old Odermatt, who won the opening downhill in Beaver Creek earlier this month, powered down a shortened Saslong course in one minute and 24.48 seconds, 0.15 ahead of early pacesetter and fellow Swiss Franjo von Allmen.
Local favourite Dominik Paris took third place, 0.19 off the pace.
"It's a great achievement, but on Saturday we have the race from the top, so we'll just have a quick toast," said Odermatt.
The start of the race, which was standing in for a cancelled downhill in Beaver Creek earlier this season, was delayed by over an hour due to poor visibility in the upper part of the course. It was worth the wait for Odermatt, who has now won five of the eight races he took part in this season.
The four-time overall World Cup reigning champion recovered from a minor blip in the middle of the course to clinch his sixth downhill victory, a year after prevailing in Val Gardena.
With 50 wins, he sits in fourth place in the list of men's all-time World Cup race winners, led by the late Ingemar Stenmark (86).
Odermatt now leads the overall World Cup standings with 605 points, with Norway's Henrik Kristoffersen in second place, 303 points behind.
Norway's Fredrik Moeller, who won a super-G in Bormio last season, crashed heavily after taking a spin during a jump.
He was flown by helicopter to the Bolzano hospital.
"Fredrik is badly bruised and has lost two teeth, and is doing well under the circumstances. He is being closely monitored by the hospital and the Ski Federation's health team to rule out injuries after such a severe crash as he has been through," national team doctor Marc Strauss said.
Thursday's downhill was the first of three speed races on the Saslong, followed by Friday's super-G and Saturday's full-length classic downhill.
With five race days in a row, speed events in Val Gardena being followed directly by Alta Badia's men's giant slalom and slalom, organisers shortened Thursday's downhill to ease the physical strain on the athletes in an Olympic season.
The men's Olympic races at the February 6-22 Milano Cortina Winter Games will be held in Bormio.