Already overriding favourite, the exit of two players posing big threats to the American saw one bookmaker price her nearest rival as far out as 19/1.
The biggest shock came on Court Two, where third seed and former champion Sharapova was knocked out by Portugal's Michelle Larcher de Brito.
The world number 131 won 6-3 6-4 against the Russian, who was impeded by what appeared to be a hip injury after falling awkwardly.
"I'm really excited," Larcher de Brito said. "I really can't believe it. It's a little bit of shock and excitement.
"I'm just really happy I got through that match. It was a really great win for me. I'm feeling really excited.
"I just take it one match at a time. I don't like to get ahead of myself. I don't like to think semi-finals.
"I've always taken it one match at a time, one tournament at a time. I just want to keep going and keep doing my best.
"I want to do as well as I can do, not get ahead of myself."
While Sharapova saw her hopes ended, second seed Azarenka did not even make it onto the court.
The Belarusian's scheduled date with Flavia Pennetta was called off due to the knee injury sustained in a first-round victory over Maria Joao Koehler on Monday.
The 2011 champion Petra Kvitova was also the beneficiary of a withdrawal, as Yaroslava Shvedova of Kazakhstan failed to show for her appointment with the Czech due to injury.
Caroline Wozniacki, Denmark's former world number one, managed to carry on after suffering a foot injury early in her match against Kvitova's compatriot Petra Cetkovska.
But Wozniacki, with her movement affected, was well beaten, going down 6-2 6-2, and it was clear she put the result largely down to her injury.
"When you can't play at 100 per cent, it's difficult," the Dane said.
"It's frustrating because you feel like you have some momentum. I feel like I'm hitting the ball well. I can play well on the grass.
"There's not really much you can do about those things."
Canadian Eugenie Bouchard knocked out Serbian 12th seed Ana Ivanovic 6-3 6-3, and Puerto Rican Monica Puig followed up her first-round win over fifth seed Sara Errani by ousting Spain's Silvia Soler Espinosa 6-2 5-7 6-4.
American Sloane Stephens beat Andrea Petkovic after a long battle, coming through 7-6 (7/2) 2-6 8-6 against the German.
Vesna Dolonc knocked out 16th seed Jelena Jankovic 7-5 6-2, while there were also wins for Kirsten Flipkens, Alize Cornet and Sorana Cirstea.
Marion Bartoli, Karin Knapp, Carla Suarez Navarro, Ekaterina Makarova and Eva Birnerova also won in the second round on Wednesday.