Nishikori saw off France's world number 547 Julien Benneteau 4-6, 6-4, 6-4, 6-2 on Centre Court and goes on to meet Russia's Andrey Kuznetsov.
"I started playing more aggressive and more solid," said the 26-year-old Nishikori who has never got beyond the Wimbledon fourth round.
"It wasn't an easy match. He started well so it was a great match for me."
Nineteen-year-old Bencic became the highest-ranked casualty at Wimbledon when the seventh seed retired from her second round match against American qualifier Julia Boserup.
Bencic, who missed the clay court season with a back injury, had only completed her first round match late Wednesday and struggled Thursday with what appeared to be a wrist problem.
Boserup, 24, goes on to face Andrea Petkovic of Germany or Russia's Elena Vesnina for a place in the last 16.
Spain's David Ferrer, the 13th seed, lost to fellow 34-year-old -- and grass court specialist -- Nicolas Mahut 6-1, 6-4, 6-3.
Canadian sixth seed Milos Raonic, regarded as a dark horse for the title, brushed past Andreas Seppi 7-6 (7/5), 6-4, 6-2.
Sock's compatriot Sam Querrey, the 28th seed, eased past Thomaz Bellucci of Brazil 6-4, 6-3, 6-2 for the dubious honour of facing defending champion Novak Djokovic for a place in the last 16.
Later Thursday, world number two Andy Murray takes centre
stage when the 2013 champion faces Taiwan's Lu Yen-Hsun.
Lu made the quarter-finals in 2010 beating former runner-up Andy Roddick on the way.
The world number 76 underwent right elbow surgery in January and missed the first four months of the season.
- Battering -
He returned in May and is currently on an 11-match winning-streak on grass at all levels having won two Challenger titles prior to coming to Wimbledon.
Sixty singles matches were scheduled for Thursday after only 90 minutes of action was possible on the outside courts on Wednesday.
In an indication of the battering the schedule had taken, the first round was only completed just before 1pm (1200GMT) when Barbora Strycova beat Anett Kontaveit.
Five-time women's champion Venus Williams ignored her exile to Court 18 to battle past Greek qualifier Maria Sakkari 7-5, 4-6, 6-3.
Williams, the 36-year-old eighth seed, next plays Russian 29th seed Darya Kasatkina for a place in the last 16.
There were also second round wins for Romanian fifth seed Simona Halep and ninth-seeded American, Madison Keys.
Later Thursday, French Open champion and last year's runner-up Garbine Muguruza, the second seed, faces experienced Slovakian player Jana Cepelova.
Highly-regarded Austrian teenager Dominic Thiem, seeded eight, takes on the Czech Republic's Jiri Vesely, who shocked Djokovic in Monte Carlo this year.
Australian Bernard Tomic, the 19th seed, is bidding for his 150th Tour-level match-win when he takes on Moldovan qualifier Radu Albot, who recorded his first Grand Slam singles match-win -- and Tour-level grass court victory -- in the first round.
A leading learning disability charity has called on him to apologise.
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