Halfback Casey will sit out on Saturday because of concussion suffered in a challenge by former Munster teammate RG Snyman, which saw him leave the field on a stretcher.
Leinster hooker Sheehan sustained suspected ligament damage to his left knee as he tackled Springboks lock Eben Etzebeth.
The extent of the injury wasn't revealed by Irish officials but Irish media suspected it was a ruptured anterior cruciate ligament, which would put him in doubt of playing in the 2025 Six Nations.
Conor Casey is helped from the field after his injury at Loftus Versfeld Stadium. (AP PHOTO)
Ronan Kelleher would be expected to start at Kings Park Stadium with Rob Herring promoted to the reserves. Heffernan's seventh and last cap was in 2022 against New Zealand.
Ulster No.9 Nathan Doak and Connacht forward Dave Heffernan have been drafted into the squad.
"Following medical assessments after Saturday's opening Test, the Ireland management can confirm that neither Craig Casey (concussion) nor Dan Sheehan (left knee) will play any further part in the South African series which concludes next Saturday in Durban," a statement from the Irish Rugby Football Union said.
"Connacht hooker Dave Heffernan and Ulster scrum-half Nathan Doak have been called up and the duo have linked up with the squad in Durban."
Doak is uncapped but has been around the senior squad for 18 months. He'll give coach Andy Farrell an option beside Conor Murray, who finished the first Test, and Connacht's Caolin Blade, who has two caps.
Ireland officials said there would be an update later in the week on other players injured in Pretoria, including Robbie Henshaw, Jamie Osborne, Bundee Aki, James Lowe and Andrew Porter.
Six Nations champions Ireland already came south without Jamison Gibson-Park, Hugo Keenan, Iain Henderson, and Jack Conan.
They went down 27-20 to the world champions on Saturday despite scoring two tries inside the final six minutes as the hosts survived a concerted fightback.
With AP.
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