The 38-year-old offspinner had Pragyan Ojha caught at slip by Mahela Jayawardene at Galle International Stadium on Thursday, slowly building pressure on the Indian tailender with four fielders around the bat.
The wicket was the last to fall in India's second innings, meaning Sri Lanka needed only 95 runs to win with more than a session of play remaining.
Muralitharan needed eight wickets in his final test to reach the 800 mark. After a five-wicket haul in the first innings, and one in the second innings on Wednesday, he claimed Harbhajan Singh early on Thursday before a long wait for his last.
A controversial figure since his unorthodox bowling action was called into question in 1995, Muralitharan has endured to become the most prolific bowler in the sport, by a long way.
Only one other man has taken more than 619 test wickets - retired Australian legspinner Shane Warne once held the world record for most test wickets at 709.
Before the match, Muralitharan admitted to having some nerves but nothing more than he'd weathered in the past.
"There is a little extra pressure on me, it being my last game, but playing under pressure is not new for me and I am just keen to go out there and enjoy myself," he said in a pre-match interview. "It would be nice to take 800 wickets."
He certainly made the most of the occasion.
Muralitharan was hoisted onto the shoulders of his team-mates and carried from the field after dismissing Ojha as the Sri Lankans celebrated for him.
He held up the match ball to the crowd to acknowlege the cheers.
