Sharapova has dropped just seven games in her three matches thus far and the imperious Russian will be confident of winning her sixth grand slam in the absence of her nemesis Williams.
The 27-year-old is on the wrong end of a 16-2 head-to-head record against the American with her only two triumphs coming in 2004, the first of which saw her crowned Wimbledon champion.
Williams crashed out 6-1 3-6 4-6 against France's Alize Cornet in the third round on Saturday, her earliest exit at Wimbledon since losing in the same round in 2005.
Her defeat came a day after Chinese two-times grand slam winner Na was dumped out 6-7(5) 6-7(5) by the Czech Republic's Barbora Zahlavova Strycova.
Their defeats have opened the door for a host of women, but the top of that list is Sharapova.
Players have long talked about the difficulty of adapting to the grasscourts of Wimbledon so soon after a long claycourt season and nobody has backed up winning the French Open with Wimbledon triumph since Williams in 2002.
Maria Sharapova reacts after defeating Alison Riske of the US in their women's singles tennis match at the Wimbledon. (Reuters)
Sharapova's form, however, suggests she can match that achievement and win her sixth grand slam in the process.
"Well, this is only my second time trying to do that. Of course, the transition, it's no secret, it's very difficult," she said after reeling off 11 consecutive games to beat Alison Riske 6-3 6-0 in the third round on Saturday.
"But I'm quite happy with the way I've gone about things so far.
"You never know what to expect. Each match poses its different challenges. I'm happy I've gone further than last year, erasing those memories and trying to form new ones.
"A Grand Slam stage, when you're playing for two weeks, seven matches within those two weeks, you're always kind of rolling with each round.
"Once you get to another (grand slam), one of the toughest things is you start from scratch, you start from the first match.
"Mentally that's always, you know, a bit more difficult because you achieve some great success, then you get on the train, come here, and right away the mentality switches that I've got to start from the first round.
"That's always a quick switch that you need to make mentally. That transition has always been quite tough for me," added Sharapova who plays German ninth seed Angelique Kerber in the round of 16.
Higher seeds remain but Sharapova's biggest challenge is likely to come in the shape of rising star Eugenie Bouchard, a semi-finalist in the last two grand slams at the Australian and French Open.
The aggressive 20-year-old Canadian faces Williams' conqueror Cornet in the next round with a potential quarter-final against Sharapova the prize.
"I wouldn't consider myself deep into Wimbledon at this stage," Bouchard said after beating Germany's Andrea Petkovic on Saturday.
"I'm into the second week, which is great. But, you know, I want to go so much further. At the same time I'm focused on one match at a time.
"But, of course, Wimbledon is probably the most prestigious tournament in the world. It's a special place to be here and I would love to stay a really long time."
Romania's third seed Simona Halep, runner-up to the Sharapova at the French Open, and Polish fourth seed Agnieszka Radwanska are expected to make extended runs in the championship.
They face Kazakhstan's Zarina Diyas and Russian Ekaterina Makarova in the round of 16 respectively.
Elsewhere German 2011 champion Petra Kvitova plays China's Shuai Peng, Czech Lucie Safarova is against compatriot Tereza Smitkova, and Danish former world number one Caroline Wozniacki faces Zahlavova Strycova.
The other round of 16 encounter will pit 2008 French Open winner Ana Ivanovic or 2013 Wimbledon runner-up Sabine Lisicki against America's Madison Keys or Kazakhstan's Yaroslava Shvedova after both of their third round matches were disrupted by bad light on Saturday.