The world number one needed three hours and 20 minutes to battle past fifth seed Nishikori 6-7 (9/11) 6-4 6-4, with the first set alone taking 85 minutes.
Murray frequently looked exhausted but dug into his seemingly-endless well of fighting spirit to win a stand-out match at an event that has been starved of such encounters.
It is the first time since the tournament moved to the O2 Arena in 2009 that Murray has won both his opening two matches and he is now in pole position to reach the semi-finals.
That could come as early as Wednesday evening if Marin Cilic defeats US Open champion Stan Wawrinka.
Novak Djokovic is already through and defeat against Nishikori would have severely harmed Murray's chances of holding onto top spot in the rankings.
The Scot said: "I just fought really hard. Kei was making me run a lot, he was dictating a bunch of the points. I managed to get enough breaks to win it.
"That's what you work for is these moments in places like this. It was an amazing atmosphere.
"I feel okay right now. It's normally the next day when you feel stiff and sore but there's hopefully three days left in the season and I'll give my best to get through as many matches as I can."
Murray found himself under pressure in the early stages, swiping angrily at the court before saving break points in successive games.
There were some good moments from the world number one but also more errors than he would have liked.
He saved another break point at 5-5 and then created his first chance, a set point, in the next game but netted a forehand.
Murray was in big trouble when he lost successive points on serve to trail 6-3 in the tie-break but Nishikori could not take either chance on his own delivery, narrowly missing a forehand on the first.
Still the fifth seed looked certain to clinch the set when Murray left an attempted lob short but the Scot somehow scrambled to return the ball and send it past a despairing Nishikori.
The crowd roared but ultimately it counted for nothing as, on Nishikori's fifth set point, Murray, not for the first time, sent a forehand wide.
Fighting through long matches is a Murray speciality and he found the perfect response by breaking the Nishikori serve in the opening game of the second set.
The Japanese player still had the edge off the ground, though, and it was no real surprise when he broke back to make it 4-4.
Nishikori had tortured Murray with the drop shot in New York but two ill-advised ones here allowed the top seed to take the advantage straight back.
That left him serving for the set and, after a hugely tense set of exchanges, he finally stumbled over the line.
Murray has played more matches than ever before this season and he looked drained but Nishikori's decision-making was clouded by fatigue and he helped his opponent to another break in the third game of the decider.
When a double fault made it 4-1 to Murray, finally the top seed had some breathing space and the end was in sight.
Nishikori showed commendable resolve to retrieve one break but Murray served it out at the second time of asking.
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