Lars Vilks had lived under police protection since depicting Islam’s revered figure with the body of a dog in 2007.
The 75-year-old died on Sunday in an accident near the southern town of Markaryd, Swedish police said in a statement.
The car, which had left Stockholm and was heading south, veered into the path of the truck and both vehicles burst into flames.
Two police officers were also killed.
The truck driver was flown to a hospital with serious injuries.
Police said they did not know why the car drove into the wrong lane but they were investigating whether a tyre might have exploded.
The car transporting Vilks had puncture-proof tyres, police said. However, exploded tyre remains were reportedly found on the road.
“This is a very tragic incident. It is now important to all of us that we do everything we can to investigate what happened and what caused the collision,” the police statement said.
“Initially, there is nothing that points to anyone else being involved.”
Born in 1946 in Helsingborg in southern Sweden, Vilks worked as an artist for almost four decades and rose to fame after producing several controversial works.
He was largely unknown outside of Sweden before 2007 when he drew sketches of the Prophet Muhammad with a dog’s body.
The Prophet Muhammad is deeply revered by Muslims and Islam forbids any kind of visual depiction of him.
Since the publication of the cartoons, Vilks had been living under round-the-clock police guard following threats against his life.
In 2010, two men tried to burn down his house in southern Sweden.
In 2014, a woman from the US state of Pennsylvania pleaded guilty in a plot to kill him.
A year later, one person was shot dead by a lone gunman in Copenhagen, Denmark, at a meeting meant to mark the 25th anniversary of an Iranian fatwa against British writer Salman Rushdie, which Vilks attended. Vilks was widely seen as the intended target.
Vilks had said that the cartoons were not deliberately intended to provoke Muslims but to challenge the boundaries of political correctness in the art world.
In an interview with Esquire magazine in 2015, he said: “In Sweden, we love dogs, so when you have a dog exhibit, everything is very nice. But in the Middle East, dogs can be seen as unclean because of religious dogma. I wanted to remind people of that. That’s when I came upon the combination and drew the Prophet as a roundabout dog, a positive dog.”