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* [[Bruce Dern]] vai [[George Spahn]]
* [[Emile Hirsch]] vai [[Jay Sebring]]
* [[Scoot McNairy]] vai Business Bob Gilbert: {{Cast list break|A fictional cowboy character on ''Bounty Law''.}}
* [[Luke Perry]] vai [[Wayne Maunder]]
* [[Luke Perry]] vai [[Wayne Maunder]]: {{Cast list break|An actor who co-starred as Scott Lancer on the TV western ''[[Lancer (TV series)|Lancer]]''.}} Perry died on March 4, 2019, from a stroke but had completed filming his scenes.
* [[Damon Herriman]] vai [[Charles Manson]]: {{Cast list break| The infamous leader of the "Manson Family", who ordered the murder of Sharon Tate and her friends.}}
* [[Austin Butler]] vai [[Tex Watson|Charles "Tex" Watson]]: {{Cast list break| A central member of the "Manson Family" who, alongside three other members, was directly involved in the Tate murders.}}
* [[Lena Dunham]] vai [[Catherine Share]]: {{Cast list break|A member of the "Manson Family" who was not directly involved with the Tate murders.}}
* [[Nicholas Hammond]] vai [[Sam Wanamaker]]: {{Cast list break|An actor–director who had moved to London in 1950 out of fear of being [[Hollywood blacklist|blacklisted]].}}
* [[Spencer Garrett]] vai Allen Kincade: {{Cast list break|The television personality and interviewer to Hollywood's elite.}}
* [[Mike Moh]] vai [[Lý Tiểu Long]]
* [[Mike Moh]] vai [[Bruce Lee]]: {{Cast list break|The international actor and stuntman who choreographed fight scenes for ''[[The Wrecking Crew (1968 film)|The Wrecking Crew]]'', which starred Sharon Tate. Following the Tate murders, Lee attended her funeral and was also privately investigated.}}
* [[Timothy Olyphant]] vai [[James Stacy]]
* [[Timothy Olyphant]] vai [[James Stacy]]: {{Cast list break| An actor who co-starred as Johnny Madrid Lancer on the TV western ''Lancer''.<ref name="ouatihesquire">{{cite news |last1=Coates |first1=Tyler |title=The Real-Life People Portrayed in Once Upon a Time in Hollywood|url=https://www.esquire.com/entertainment/movies/g26888375/once-upon-a-time-in-hollywood-cast-photos/ |accessdate=March 23, 2019 |work=Esquire |date=March 21, 2019}}</ref>}}
* [[Maurice Compte]] vai Land Pirate Mao
* [[Lew Temple]] vai Land Pirate Lew
* [[Lorenza Izzo]] vai Francesca Cappucci
* [[Rafał Zawierucha]] vai [[Roman Polanski]]: {{Cast list break| An acclaimed filmmaker and Tate's husband, who was in Europe working on a film when Tate was murdered.}}
* [[Costa Ronin]] vai Wojciech Frykowski
* [[Costa Ronin]] vai Wojciech Frykowski: {{Cast list break| A screenwriter and friend of Roman Polanski, who, alongside his lover Abigail Folger, was murdered in Tate's home by followers of Charles Manson.}}
* Samantha Robinson vai Abigail Folger
* Samantha Robinson vai Abigail Folger: {{Cast list break| Wojciech Frykowski's lover, as well as heiress to the [[Folgers|Folger coffee fortune]]. She was murdered in Tate's home by followers of Charles Manson.}}
* [[Rumer Willis]] vai [[Joanna Pettet]]: {{Cast list break| An actress and friend of Sharon Tate, who had lunch at Tate's home, mere hours before the murders took place.}}
* [[Dreama Walker]] vai [[Connie Stevens]]: {{Cast list break| An actress who lived near Sharon Tate and [[James Stacy]]'s ex-wife.}}
* [[Margaret Qualley]] vai Mèo Kitty
* [[Victoria Pedretti]] vai Lulu
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