The 28-year-old New Zealander, who was signed from the Auckland Blues in March, made two appearances as the All Blacks went on to win Rugby World Cup two weeks ago.
Hooker Rory Best and blindside flanker Stephen Ferris will make their first starts for Ulster this season after being rested following their exertions at the World Cup with Ireland.
Scrum half Ruan Pienaar picked up a hamstring injury in training this week and is likely to be out for four to six weeks.
He made his first appearance of the season against the Scarlets last Saturday, having been on World Cup duty with South Africa.
Paul Marshall, who started the opening six league games, will replace Pienaar in the number 9 jersey, with Ian Porter taking his position on the replacements bench.
This week Darren Cave gets a chance to partner Paddy Wallace in midfield, with Nevin Spence named among the replacements. The back-three of Craig Gilroy, Andrew Trimble and Simon Danielli remains unchanged from last weekend.
Best and Afoa are joined by Tom Court to make up an all-International front row, while lock Johann Muller will continue as captain. Ferris' inclusion sees Pedrie Wannenburg move to number 8, with Chris Henry starting at openside flanker.
Connacht have only beaten Ulster once in the past eight seasons and have not won in Belfast since 1960. Even so, Ulster head coach Brian McLaughlin is not taking anything for granted.
"Connacht have a settled team and have started the season very well. Three wins and three losing bonus points suggests that they are going to be very difficult opposition, but we know that already," he said.
McLaughlin is delighted to be able to call on Afoa just a few days after his arrival in Belfast. "It was crucial that John got to know our structures and our system straight away so he has had a couple of training sessions already.
"We are looking forward to seeing him play and looking forward to seeing what he can add to our game.
"We're delighted to have Stevie (Ferris) and Rory (Best) back in the team too. Stevie hasn't played for us since January so it's a big day for him.
"He brings great energy and physicality to the team and it's brilliant to have him available with some massive games coming up.
"To have Rory in there too is excellent. It helps Johann as far as leadership is concerned and we are very hopeful that he can bring his World Cup form to Ravenhill at the weekend and get us back on the right track.
"When you lose someone of Ruan's calibre it's obviously a blow, but Paul Marshall has done brilliantly so far this season and when he was asked to play last season, so we're happy with the situation."
Tickets are still available for Saturday's derby game. Call 02890493222 (ticketing) or click here to purchase your tickets now.
Family packages are available from just £49 for two adults and two children. Ulster Rugby now have an exclusive ticketed marquee with packages available from just £45. Click here for more details.
ULSTER (v Connacht): Simon Danielli; Andrew Trimble, Darren Cave, Paddy Wallace, Craig Gilroy; Ian Humphreys, Paul Marshall; Tom Court, Rory Best, John Afoa, Johann Muller (capt), Dan Tuohy, Stephen Ferris, Chris Henry, Pedrie Wannenburg.
Replacements: Andi Kyriacou, Paddy McAllister, Adam Macklin, Lewis Stevenson, Robbie Diack, Ian Porter, Nevin Spence, Adam D'Arcy.