Roger Federer will be seeking a 13th appearance in the US Open quarter-finals when he plays Australian John Millman.
Federer, the second seed, escaped the worst of the conditions as he headlined the night session on Ashe.
Novak Djokovic called for the doctor during the second set against Adrian Mannarino but put aside his discomfort to progress 4-6, 6-2, 6-1.
The world number one Spaniard was untouchable as he schooled Paire for the fourth time without a loss, taking 74 minutes as he broke six times.
Nadal had recently lost to Novak Djokovic in the second-longest Wimbledon semi-final ever played.
Alexander Zverev joined a list of back-to-back ATP Washington Open champions that includes Andre Agassi, Michael Chang and Juan Martin del Potro.
Alexander Zverev will face 10th-seeded Greek 19-year-old Stefanos Tsitsipas in the ATP Washington Open semis.
Muguruza's defeat leaves just top seed Simona Halep, number seven Karolina Pliskova and 10th seed Madison Keys as the remaining top-ranked contenders after two rounds.
Dominic Thiem on Tuesday cruised into the semi-finals of the French Open defeating Alexander Zverev in straight sets.
Djokovic eased past Spanish veteran Verdasco 6-3, 6-4, 6-2 and will play in the last eight at Roland Garros for a record 12th time.
World number 38 Khachanov has now lost at the last-16 stage at Roland Garros twice in a row, while Zverev ended his wait for a maiden major last-eight appearance at the 12th attempt.
Zverev is looking to become the first German man to win the title since 1937
In all the four Slams, it's only the sixth time in the Open era that the defending champion has perished at the first hurdle.
Alexander Zverev has emerged as the main threat to Rafael Nadal's French Open crown in recent weeks as he bids to end Germany's 81-year wait for a men's singles title at Roland Garros.
Top seed Nadal raced away with the last five games to secure a 32nd Masters title and ensure a return to the world number one spot.
Alexander Zverev got his Rome title defence underway at the Italian Open on Wednesday with a straight-sets win over Italy's Matteo Berrettini as the German bids for back-to-back Masters triumphs after success in Madrid.
Roger Federer returns to the top spot despite not having played since March.
Alexander Zverev has long been marked out as a future star of the men's game and his victory suggests the German can be a major threat at the French Open later this month.