Vonn, who is 28 points clear of nearest rival Lara Gut, announced Wednesday that her campaign is over after fracturing her knee in action last week.
The American ski star was evacuated off the slope by sled after crashing during a super-G event in Andorra Saturday -- although she did return to competition 24 hours later in a knee brace.
"Because I am currently leading the Overall World Cup standings, this is one of the toughest decisions of my career," she posted in a statement on Instagram.
"Further damage to any of the fragments could result in a serious surgery that would risk my future in ski racing."
Despite setting the fastest time in the super-G leg and finishing 13th in the combined event Sunday, scans have since revealed that Vonn suffered three fractures to her tibial plateau -- rather than one that original tests first showed after the crash.
The four-time overall winner, who has captured 76 World Cup races in total, will miss the remaining 2016 World Cup meetings in Slovakia and Switzerland, which run until March 20.
"I have made the decision to end my season. I am very proud of what I have been able to accomplish this year," Vonn added in her statement.
"With the World Championships in St. Moritz next year and the Winter Olympics in South Korea the following year, I cannot take that risk [of suffering further damage]."
Vonn is 31 years old and already has an extensive injury history, including the torn ACL/MCL and fractured tibial plateau she suffered during the World Championships in February 2013.
Vonn hasn't only made her mark on the slopes. She's also been in the news for dating golf great Tiger Woods and, more recently, for posing only in body paint for the Sports Illustrated swimsuit issue. Woods and Vonn are no longer a couple.