Jake White's side arrive at Twickenham aiming to end a losing run of five successive defeats against the world champions.
With so much at stake, Saturday promises to be a ferocious encounter and Lewsey knows the Springboks have players capable of making England pay for the embarrassing flop in Dublin.
"One of the worst things you can do against a good side is score or beat them because that just upsets them and they come back even more determined,"
"And I know how we'd react if we lost the week before - we'd want to rectify things.
"They want to finish their season on a high and beat us. They will be massively motivated and have the players to cause a huge amount of damage."
England boss Andy Robinson is determined to inject some much-needed creativity and flair into his side's attacking play.
They had few problems creating openings against Canada in last Saturday's 70-0 triumph but South Africa are a different kettle of fish altogether and try-scoring opportunities are likely to be at a premium.
But Lewsey said: "If we're to emulate what we did last year and win the World Cup in 2007 we need to start pushing the boundaries again. We played well against Canada and must continue that.
"But playing good rugby is not just about moving the ball wide.
It's about choosing the right options and being unpredictable.
"If you play by numbers and stick to a set plan it's very easy to defend against - you'd be crucified by South Africa's blitz defence."
Wasps forward Joe Worsley will return after a leg injury with Gloucester forward Andy Hazell, who made an encouraging debut against Canada, dropping to the bench.
Robinson has otherwise retained the side that comfortably accounted for the Canadians, although Leicester's uncapped scrum-half Harry Ellis has won a bench place.
Jason Robinson keeps the captaincy in light of Jonny WIlkinson's continuing injury.
Springboks coach White has made one enforced change, with wing Jean de Villiers promoted to replace Ashwin Willemse.
England: J Robinson (capt); M Cueto, H Paul, M Tindall, J Lewsey); C Hodgson, A Gomarsall; G Rowntree, S Thompson, J White, D Grewcock, S Borthwick, J Worsley, L Moody, M Corry.
Replacements: A Titterrell, A Sheridan, B Kay, A Hazell, H Ellis, W Greenwood, B Cohen.
South Africa: P Montgomery ; B Paulse, M Joubert, D Wet Barry, J de Villiers; J van der Westhuyzen, F du Preez; O du Randt, J Smit (capt), E Andrews, B Botha, V Matfield, S Burger, A J Venter, J van Niekerk.
Replacements: H Shimange, C J van der Linde, D Rossouw, G Britz, M Claasens J Fourie, B Habana.
Humphreys has point to prove
Ireland's record points-scorer David Humphreys - set for his first international start in 13 months - is treating his 65th cap against the United States on Saturday as if it were his last.
All seven replacements in last weekend's historic 17-12 defeat of South Africa at Lansdowne Road have earned a recall to coach Eddie O'Sullivan's starting line-up and Humphreys, 33, is one of many with a point to prove.
Munster's Frankie Sheahan - without a start in two years - Marcus Horan and Donncha O'Callaghan, Leinster duo Guy Easterby and Eric Miller and 65-cap veteran Kevin Maggs, now of Ulster, all earn rare starts along with Humphreys, with O'Sullivan insisting: "The team for Argentina isn't picked yet.
"There are guys who are coming into the team now who are chomping at the bit. Maybe they haven't had a lot of Test rugby or have been coming off the bench."
Ireland face Argentina in Dublin on Saturday week - coincidentally the same opposition as when Humphreys last started for Ireland during last year's World Cup.
O'Sullivan added: "These fellas have a point to prove - South Africa is done and dusted, it was a great performance but it's yesterday's news now. We raised our standards against the Springboks and the trick now is to maintain them. That's the benchmark."
Humphreys, who will break through the 500-point barrier against the Americans with a nine-point haul, said: "We've got to get the focus right on the day. The US may be classed as weaker opposition, but we'll treat them with the respect they deserve.
"Every international game could be my last one, so that's the way I look at it. I'll enjoy it by playing well and winning. My first priority is always to go out, play well and enjoy it, and try to bring the best out of the younger players who have a huge opportunity on Saturday."
Both Humphreys' Ulster colleague Tommy Bowe and Munster flanker Denis Leamy will make their senior debuts against the 16th-ranked Eagles.
USA coach Tom Billups has made four changes, one positional, to the side that lost 39-31 to France in Connecticut in July.
Lock Alec Parker, blindside flanker Brian Surgener and right wing Al Lakomskis return, with captain Kort Schubert of the Cardiff shifting to number eight.
"We have to get a lot of things right on the day," admitted former Eagles captain Billups.
"We're looking for a good performance and a smart one in the conditions."
Ireland: G Murphy; S Horgan, B O'Driscoll, K Maggs, T Bowe; D Humphreys, G Easterby; M Horan, F Sheahan, J Hayes, D O'Callaghan, P O'Connell, S Easterby, D Leamy, E Miller.
Replacements: S Byrne, S Best, L Cullen, A Foley, P Stringer, R O'Gara, G Dempsey.
USA: F Viljoen; A Lakomskis, P Emerick, S Sika, D Fee, M Hercus, M Timoteo, M McDonald, M Wyatt, J Waasdorp, A Parker, G Klerck, B Surgener, T Petruzzella, K Schubert(captain).
Replacements: M Hobson, C Osentowski, J Gouws, F Mo'unga, D Williams, M Sherman, A Tuipulotu.
Williams sticks to his guns
Scotland coach Matt Williams has named an unchanged team for the third autumn Test against Australia at Hampden Park on Saturday.
The Scots crushed Japan 100-8 at McDiarmid Park last weekend and the Aussie-born Williams will field the same XV in Glasgow.
The one squad change sees prop Bruce Douglas on the bench in place of Craig Smith.
Williams has also called for the fans to create the same atmosphere at Hampden as they did in Perth.
He said: "It would be wonderful if we could get a big enough crowd at Hampden to get behind the team in the same manner as the crowd at Perth last weekend.
"My plea would be to come and support your team. It really makes a difference."
Australia have made one change to their starting line-up for this weekend's Test against Scotland at Hampden Park with David Lyons taking over as number eight from the injured John Roe.
There are also two new faces on the replacements bench from the side that lost 27-14 to France in Paris last Saturday with Radike Samo and Stephen Hoiles being brought in.
Flanker Hoiles comes into the 22 for the first time after impressing coach Eddie Jones during Tuesday night's match between Australia A and the French Barbarians, which the tourists won 45-15.
Roe misses out after sustaining a minor neck injury in training and he could be sidelined for the remainder of Australia's tour.
"John Roe had a good game last week against France but unfortunately he has a neck problem at the moment which has ruled him out for this match and then possibly the England Test," said Jones.
"With David Lyons putting in a strong performance against the Barbarians he deserves an opportunity to get his starting spot back."
The match should see Australia fullback Chris Latham win his 50th Test cap having made his debut against France in 1998.
"I started the season with a goal of reaching my 50th cap this year and it's something I'm really excited about," said Latham.
"We all know we need to put in a much better performance this weekend against Scotland. The Australia 'A' guys led the way last night, and everyone is focused and keen to play well and make up for last week," he added.
Scotland: H Southwell; C Paterson, B Hinshelwood, A Henderson, S Lamont; D Parks, C Cusiter; A Jacobsen, G Bulloch, G Kerr, S Grimes, N Hines, A Hogg, J Petrie, D Macfadyen.
Replacements: R Russell, B Douglas, S MacLeod, J White, M Blair, G Ross, G Morrison.
Australia: C Latham; C Rathbone, S Mortlock, M Giteau, L Tuqiri; S Larkham, G Gregan (cap); B Young, J Paul, A Baxter, J Harrison, D Vickerman, G Smith, P Waugh, D Lyons.
Replacements: M Dunning, B Cannon, R Samo, S Hoiles, E Flatley, M Rogers, W Sailor.