In 1972, Bugliosi left the District Attorney's (DA) office and started a private practice, which included defense cases for criminal trials.

As a Los Angeles County Deputy District Attorney, Bugliosi came to national attention for prosecuting the seven murders that took place August 9–10, 1969, in which Sharon Tate, Jay Sebring, Abigail Folger, Wojciech Frykowski, Steven Parent, and Leno and Rosemary LaBianca were killed.

Bugliosi successfully prosecuted Charles Manson, Tex Watson, Susan Atkins, Patricia Krenwinkel, and Leslie Van Houten for these murders, and each was convicted.

He was credited especially with gaining conviction of Manson, who, although he had tied up the La Biancas, had not been physically present during the actual murders.

[3] In 1972, Bugliosi ran as a Democrat for Los Angeles County District Attorney against longtime incumbent Joseph Busch.

Bugliosi ran again in 1976, after Busch died of a heart attack in 1975, but lost to interim District Attorney John Van de Kamp, who was incumbent.

He used his profiles to explore what he considers broader problems in American criminal justice, the media, and the political appointment of judges.

In his book, No Island of Sanity, he argues that the right of a president to be free of a private lawsuit while in office outweighed Paula Jones's interest in having her case brought to trial immediately.

In 1986, Bugliosi played the part of prosecutor in an unscripted 21-hour mock television trial of Lee Harvey Oswald.

It also included a former Texas judge and a jury of U.S. citizens from the Dallas area which reviewed hundreds of exhibits and listened to witnesses who testified about the assassination.

"[9] The program required extensive preparation by Bugliosi and inspired him to later write a comprehensive book on the subject of the assassination.

[11] A portion of the book was re-published in 2008 as Four Days in November: The Assassination of President John F. Kennedy, which became the basis of the 2013 film Parkland.

The title of Reclaiming History derived from Bugliosi's belief that the history of the Kennedy assassination has been hijacked by conspiracy theories, the popularity of which, he asserted, has a pernicious and ongoing effect on American thought: Unless this fraud is finally exposed, the word believe will be forgotten by future generations and John F. Kennedy will have unquestionably become the victim of a conspiracy.

If that is allowed to happen, Lee Harvey Oswald, a man who hated his country and everything for which it stands, will have triumphed even beyond his intent on that fateful day in November.After leaving the district attorney's office, Bugliosi wrote, jointly with Curt Gentry, a book about the Manson trial called Helter Skelter (1974).