On April 1, 2001, Syme attended a party at musician Marilyn Manson's home. After being driven home by another party guest shortly before dawn, she left her home, reportedly to return to the party. On the morning of April 2, 2001, Syme drove her 1999 Jeep Grand Cherokee into a row of parked cars on Cahuenga Boulevard in Los Angeles. She was partially ejected from the vehicle and died instantly. Syme was 28 years old. Syme is buried next to her daughter, Ava Archer Reeves (stillborn in December 1999), whose father is the actor Keanu Reeves, in Westwood Village Memorial Park Cemetery in Los Angeles.

In tribute to Syme’s memory, David Lynch dedicated the 2001 film Mulholland Drive to her. In April 2002, Syme’s mother, Maria St. John, sued Marilyn Manson for wrongful death for giving Syme “various quantities of an illegal controlled substance” and for "instructing [Syme] to operate a motor vehicle in her incapacitated condition". Shortly after the lawsuit was filed, Manson issued a statement denying responsibility for Syme's death, stating that the lawsuit was "completely without merit". An investigation into the accident concluded that Syme, who was not wearing a seatbelt, was inebriated at the time of the accident. Reports also stated that police found two rolled up dollar bills that contained a white, powdery substance and two bottles of prescription drugs, a muscle relaxant and an anticonvulsant. Syme's mother told police her daughter was seeking treatment for back pain and depression just a few days prior to her death.