While police declined to publicly identify the two people found deceased, LA Mayor Karen Bass and California Governor Gavin Newsom each released statements confirming that Reiner, 78, and his wife, Michele, 68, had died.
"This is a devastating loss for our city and our country," the mayor wrote.
"Rob Reiner's contributions reverberate throughout American culture and society, and he has improved countless lives through his creative work and advocacy fighting for social and economic justice," the mayor wrote.
The Los Angeles Police Department issued a statement on social media calling the case an "apparent homicide".
Police had not detained anyone for questioning nor identified a suspect as of Sunday night, Deputy Chief Alan Hamilton told a press conference.
LAPD patrol officers dispatched to the home late on Sunday afternoon discovered two bodies inside the residence. Emergency personnel had first responded to a call for medical aid, a city fire department official said earlier.
Detectives of the LAPD's robbery-homicide unit were waiting for a search warrant before entering the home to conduct a thorough search and full-fledged investigation of the premises, Hamilton said, adding that a cause of death would be made public by the Los Angeles County Medical Examiner's Office.
As an actor, Reiner was best remembered for his role on the 1970s television comedy hit All in the Family as Mike "Meathead" Stivic, the son-in-law and liberal foil of the lead character, working-class bigot Archie Bunker, played by Carroll O'Connor.
The role garnered Reiner two Emmy awards for outstanding supporting actor.
Reiner went on to have a prolific Hollywood career as a director, starting with This is Spinal Tap, a 1984 mockumentary following the trials and tribulations of a fictional hard rock band on tour.
The satiric film became a cult classic, known for its mostly improvised script, with Reiner playing the faux documentary filmmaker Marty DiBergi.
The movie worked, Reiner later said, because of the cast's love for rock 'n' roll.
"That was the trick - to make fun of it and at the same time, honour it," Reiner told 60 Minutes in an interview marking the launch of this year's sequel, Spinal Tap II: The End Continues, which he also directed and appeared in.
Reiner directed nearly two dozen films in all, including classics such as Stand by Me, a 1986 coming-of-age drama about four boys who set out to find the body of a missing youth, as well as 1989's When Harry Met Sally, starring Billy Crystal and Meg Ryan.
That film, often cited as one of the greatest romantic comedies of all time, featured the famed line, "I'll have what she's having," delivered by the director's real-life mother, Estelle Reiner, playing a bit part as a diner reacting to Ryan's character faking an orgasm in a restaurant.
Versatile across a range of genres, Reiner directorial credits also included the 1987 fairy tale adventure The Princess Bride, the 1990 psychological thriller Misery, an adaptation of a Stephen King novel starring Kathy Bates and James Caan, and the 1992 military courtroom drama A Few Good Men, starring Jack Nicholson, Tom Cruise and Demi Moore.
Reiner's wife, Michele, was at one time a photographer who captured the image of Donald Trump that appears on the cover of his book Trump: The Art of the Deal.
Rob Reiner, a native of New York City and the son of the late comedy writer and actor Carl Reiner, was also well known as a Democratic Party activist and advocate of various liberal social causes.
In the 2004 presidential election, he backed Democratic candidate John Kerry and featured in advertisements taking aim at incumbent President George W. Bush. Reiner also supported Democratic presidential hopefuls Al Gore and Hillary Clinton.
He campaigned against California Proposition 8, a 2008 ballot measure that amended the state constitution to ban same-sex marriages. Prop 8 was later overturned by the courts and formally repealed by another voter initiative.
He led a separate campaign to pass Proposition 10, a state ballot initiative that created an early childhood development services program.
Reiner was first married to Penny Marshall, who played Laverne in the TV sitcom Laverne & Shirley, and was also a producer and director.
He was an adoptive father to Marshall's daughter and had three children with Michele Singer.
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