The Swiss racer held off the challenge of Susannah Scaroni to finish just short of her own world record of 1:34:16.
Debrunner, who is the athlete to beat in the women’s sport after an incredible few years, thrived in the near-perfect conditions for the wheelchair athletes on Sunday.
She didn’t have it all her own way throughout the race, with the six-time Paralympic champion facing strong competition from the chasing Scaroni, eventually pulling clear of the American who crossed the line in 1:38:08.
It is the latest chapter in what is becoming a fine battle between the pair, which Scaroni came out on top of in Boston on Monday 21 April.
Reacting to her win, Debrunner said: “I’m super proud that this is my third win at the London Marathon. I’m a very good match with this course, it was a superstrong field, the weather was great for me because I like it warm.
“There was a really strong men’s field ahead of me and they drew me along and I had to do some slalom to get ahead.”
Scaroni paid tribute to her rival after the race, saying: “She is so phenomenal, it’s fantastic to race against her as it makes it stronger, I love the fast pace, and I’ll keep trying to catch her.
“It was a very good race for me; it’s a really technical course but I really enjoyed the weather today it was perfect for me.”
Three-time London Marathon champion Manuela Schar finished third in 1:41:06.
She said: “It's amazing what is happening in the women's wheelchair racing field right now. I feel so honoured to still be part of that and to still be on the podium. I don't have a ten year plan - I just work as hard as possible and try to improve.”
British racer Eden Rainbow-Cooper was fourth in 1:44:49, matching her finish in Boston on Monday.
“It was a great race for me, although it was tough and hot. Last year I finished, but with an injury, this year I crossed with a normal amount of marathon pain.
“I'm delighted today as the injury did keep running through my mind, but I just put it to one side and focused on my rest. I’ve been working on my speed and endurance as the top three are so fast and so experienced.”
Fellow Brits Jade Jones-Hall (1:46:51) and Sammi Kinghorn (1:46:54) were sixth and seventh, respectively.