Former world champion Lewis claimed victory in a hard-fought contest which was the pick of the third-round ties in Minehead.
In battle of two former UK Open champions, Lewis emerged as a 10-8 victor against Wade, who led 3-0 in the early stages before seeing the Stoke ace finally seal his win with a 121 bull finish.
"The way that James has been playing recently has probably been as good as anyone in the world so I'm happy to come through that," said Lewis.
"We're really close in the rankings and I knew that James could have overtaken me this weekend, so when the draw came out I knew it was in my own hands.
"The pressure was on and I did the job, and I thought I played really well, especially how I scored. I'd love to win this again and I'm very capable."
The day concluded with a dramatic 10-9 win over Anderson for Basingstoke amateur Paul Hogan, a 53-year-old delivery driver who had won through the Rileys Amateur Qualifier in South Benfleet in January to earn his spot in the finals.
Having found himself 2-0 down early on, Hogan hit back to lead 7-5 before Anderson took out 136 as he levelled, but the amateur ace eventually prevailed in the deciding leg after the Scot missed the bull for victory.
Hogan then drew Lewis for a tasty fourth-round clash which will take place on Saturday afternoon and admitted: "It was a hard win. Gary's a two-time world champion and one of the best in the world so I didn't expect to win.
"That's one of the best wins I've ever had, and I'm so happy. I've just got to go up there against Adrian and play my darts again."
World number three Peter Wright, the runner-up to the currently-injured Michael van Gerwen in the past two years, followed up his brilliant Betway Premier League win on Thursday night with a 10-3 defeat of James Richardson.
Richardson won past Spain's Antonio Alcinas and amateur hopeful Neil Smith during the afternoon, but was unable to overcome the limping Scot, who defied a twisted ankle to progress.
"You don't throw with your foot, so my ankle wasn't an issue," said Wright, who won three of the UK Open Qualifiers last month to be the top-ranked professional qualifier.
"I twisted it against Adrian Lewis but I'm not going to let it affect me this weekend and I'm giving it my best shot."
Wright will now take on world number six Dave Chisnall, who picked up a 10-4 victory over Jamie Caven after the Derby ace battled past Dan Read and Ben Green to reach the last 64.
Two-time UK Open champion Raymond van Barneveld defeated Barrie Bates 10-6 in their rematch of the 2006 final.
Van Barneveld was later drawn into one of two all-Dutch fourth round ties, as he faces Ron Meulenkamp after the left-hander enjoyed wins over Hong Kong's Royden Lam, amateur qualifier Lee Evans and Kettering's Ricky Evans on Friday.
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