Several suspects were investigated in the wake of William's murder, including his former valet and cook, Edward Sands, who reportedly forged his employer's signature on checks and burgled his home. Henry Peavey, William's valet and the first person to discover his body, also came under suspicion due to his eccentricities and for being arrested for "social vagrancy" a few days before the director's murder.
Another major suspect in the case was actress Mabel Normand, who was thought to have been William's lover at the time of his death. Mabel had asked William for help in ending her cocaine addiction, and according to Robert Giroux's book A Deed of Death, he had met with federal prosecutors to prepare to testify against her drug dealers and help her sever that tie.
As such, one of the leading theories about his murder was that Mabel's dealers learned of William's intentions to out them and hired a hitman to keep him quiet. The actress was said to be the last person to see William alive, and left his home around 7:45 p.m. on February 1. Ultimately, Mabel was ruled out as a suspect and was reportedly inconsolable at his funeral.
The police's fourth suspect was Mary Miles Minter, a former child star who had worked with William and became infatuated with him, despite their 30-year age gap. It is widely believed that Mary's love was unrequited and that William rebuked her advances, but her mother, Charlotte Shelby, was reportedly overprotective of her and had threatened William in the past.
Charlotte had owned a .38 calibre pistol with a rare type of bullet that perfectly matched the one found in William's back, yet she reportedly threw the weapon into the Louisiana bayou when suspicions arose. Charlotte was also good friends with the LA District Attorney, and investigations into her possible involvement in the crime were dropped.
Although no one was ever arrested in relation to the murder, a detective on the case, William Michael Cahill, later said in a 1968 interview that "we were doing all right, and then about a week later we got the word to lay off the case", pointing to something strange afoot.