The woman, who dialed her local operator roughly 20 minutes before the shooting of the President in Dallas, stated that he was going to be shot. Jones alleged that "Karyn Kupcinet" was attempting to warn someone of the impending assassination. Jones claimed that she was told of the imminent assassination by her father, who allegedly had been given advance notice by Oswald's killer Jack Ruby, whom Irv Kupcinet had met in Chicago in the 1940s.

Regarding Irv Kupcinet's connection to Jack Ruby, one year his senior, the Warren Commission determined that many men in their age bracket had interacted with Ruby in Chicago before 1947, when he moved from Chicago to Dallas. The Commission questioned many Chicagoans who had interacted with Ruby. None of them had prior knowledge that he was going to shoot Oswald.

Kupcinet had a brief acting career during the early 1960s. Six days after the assassination of John F. Kennedy, her body was found at her West Hollywood, California, home. It has been theorized that Kupcinet's death, officially ruled a homicide, was connected to the assassination or was the result of an accidental fall. In the 1960s, Irv Kupcinet publicly dismissed the theories linking his daughter to the President's death. In 1992, The Today Show referred briefly to her alleged connection to the assassination, which prompted Kupcinet to describe the television broadcast as "an atrocious outrage" and "calumny". Karyn Kupcinet's death remains officially unsolved.

By 1961, Kupcinet was living in Hollywood and was getting positive reviews for her acting. In March 1962, a Los Angeles Times interviewer, assigned to help Kupcinet promote The Gertrude Berg Show, noted her talking exclusively about food and her weight.

In December 1962, Kupcinet filmed a guest-star appearance on The Wide Country and had her first meeting with one of the series' stars, Andrew Prine, and began a relationship with him. However, the relationship was problematic, Kupcinet was abusing diet pills along with other prescription drugs, and she had been arrested for shoplifting.

Kupcinet's death was first mentioned in connection with the John F. Kennedy assassination in 1967 by researcher Penn Jones, Jr. in the self-published book Forgive My Grief II. Jones cited an Associated Press wire Service story about an unidentified woman who placed a phone call on November 22, 1963, from the vicinity of Oxnard, California, about 50 miles North West of Los Angeles, and Jones claimed this woman was Kupcinet.

Kupcinet's last onscreen appearance was on Perry Mason in the role of Penny Ames, entitled, "The Case of the Capering Camera". The episode aired on CBS on January 16, 1964, nearly two months after her death. Ironically, it was the final on-screen appearance of Ray Collins as Lt. Tragg.

In 1971, Irv Kupcinet and his wife also founded the Karyn Kupcinet International School for Science, a summer research internships program at the Weizmann Institute of Science.

In 1988, Kupcinet's father Irv published a memoir in which he revealed that he and his wife Essee (Karyn's mother) believed that Andrew Prine had had nothing to do with Karyn's murder. He was suspicious of a person, still alive when he wrote his memoir, who had no connection to Prine.

During the production and subsequent release of Oliver Stone's film JFK, Irv Kupcinet attacked the movie and the conspiracy theories surrounding it. When the film's box-office success led to a wave of media attention about the JFK conspiracy, NBC's Today Show broadcast a list of mysterious deaths, including that of Karyn Kupcinet. Irv Kupcinet responded to the Today broadcast in his column in the Chicago Sun-Times of February 9, 1992:

On September 30, 1999, an episode of E! True Hollywood Story, entitled "Death of a Dream: Karyn Kupcinet", detailed Kupcinet's life and theories regarding her death.

In 2007, Kupcinet's niece, Actress Kari Kupcinet-Kriser, and Washburn University professor Paul Fecteau, began work on a book about Kupcinet's unsolved murder.

In 2013, the Ventura County Star commemorated the 50th anniversary of the JFK assassination with a long article about the unknown woman who had used a phone in the vicinity of Oxnard, 50 miles away from Karyn Kupcinet's home, immediately before the shooting of JFK. Citing FBI documents that were declassified decades after the events of November 1963, the Ventura County Star article claims that two telephone operators with General Telephone Company who listened to the unknown woman talking for approximately 15 minutes gave the FBI a description of her voice. FBI agents questioned the two operators a very short time after JFK's death. Their description did not match Kupcinet's voice in the slightest, especially regarding her age bracket. The 2013 Ventura County Star article adds that the two operators believed the woman on the phone was "mentally disturbed."