Webb, who played off the bench in the 34-21 victory in Johannesburg last week, comes in for Byrhandre Dolf, who is unavailable for selection because of player welfare rest protocols.
Her place on the bench will be filled by Maceala Samboya, who earned the last of her seven Test caps against the Black Ferns in their historic Women's Rugby World Cup quarterfinal in Exeter in September last year.
Like Webb, Samboya was involved with the Springbok Women's Sevens in the 2026 season, as was Lerato Makua, who also comes back into the match-23 for the first time in 2026.
The inclusion of Makua, who also played in Exeter, is one of five changes amongst the replacements. Anacadia Minnaar will take over from Felicia Jacobs at scrumhalf, Makua comes in for Faith Tshauke, and Nomsa Mokwai will take over from Anathi Qolo as lock cover, while Nombuyekezo Mdliki, another Exeter participant, takes over from Thandile Mazwi at prop.
De Bruin said the team selection was not influenced by last week's result at all.
"Dolf needed the rest and Eloise is more than capable playing in the spine, so she will slot in seamlessly," said De Bruin.
"We wanted to give as many players in our group of 30 a run in this series, hence some changes on the bench. We were looking inward at what we want to achieve on the weekend when we selected the squad."
The Bok coach is expecting a fierce backlash from the USA, who trailed 34-0 at Ellis Park before scoring three unanswered tries: "They are a very good team and will come at us. We prepared well though and will again be looking for a strong start."
Springbok Women captain Babalwa Latsha said: "We were happy with a lot of things that went well at Ellis Park, but we cannot fool ourselves thinking that will just flow over to Loftus.
"We will have to be at our very best if we want a repeat performance. The USA is a very good team, they showed that in the way they carved us up in that second half. They have very good players and we have prepared accordingly."
Latsha said home support would again be a factor.
"Most of our players call Loftus their home, while you still have the altitude factor, but more than anything we would love the crowd and home support to be the difference," she said.
"We came back from the World Cup telling people that a giant has awakened. For everyone to see and believe that, we need to show up every weekend we play and deliver. That will be our focus this weekend."
The Test kicks off at 13:30.
Springbok Women - 15 Eloise Webb, 14 Jakkie Cilliers, 13 Ayanda Malinga, 12 Aphiwe Ngwevu, 11 Alichia Arries, 10 Libbie Janse van Rensburg, 9 Unam Tose, 8 Logan Welman, 7 Catha Jacobs, 6 Sizophila Solontsi, 5 Danelle Lochner, 4 Vainah Ubisi, 3 Babalwa Latsha (c), 2 Micke Gunter, 1 Sanelisiwe Charlie.
Replacements: 16 Anushka Groenewald, 17 Yonela Ngxingolo, 18 Nombuyekezo Mdliki, 19 Nomsa Mokwai, 20 Lerato Makua, 21 Sinelitha Noxeke, 22 Anacadia Minnaar, 23 Maceala Samboya.
Four months after fearing her international career was losing momentum, Aphiwe Ngwevu has emerged with renewed confidence after embracing a hybrid role that has revitalised her place in the Springbok Women squad.
Belgium manager Rudi Garcia has praised his players after their commanding 4-1 victory in the FIFA World Cup last 16 over the United States and insisted the pre-match controversy surrounding Folarin Balogun had no influence on the result.
Belgium booked their place in the 2026 FIFA World Cup quarter-finals after a commanding 4-1 victory over the United States in Seattle, ending the co-hosts' hopes of reaching the last eight for the first time since 2002.
England manager Thomas Tuchel has criticised the lack of clarity surrounding disciplinary decisions at the 2026 FIFA World Cup after United States forward Folarin Balogun escaped a ban.
