Mathews, who has been out of international action since January this year, is likely to miss the encounter due to a calf injury. Vice-captain Upul Tharanga is the likeliest candidate to lead the team.
Though the all-rounder was declared fully fit before the team's departure for the United Kingdom, a statement from Sri Lanka Cricket (SLC) on Thursday revealed that Mathews suffered a "strain on the muscle".
Mathews' absence could jolt the prospects of the islanders, who rely on him to bring balance to the playing XI -- he often delivers 10 overs in One-Day Internationals (ODI) in addition to batting at No. 5.
The 30-year-old had also appeared to be in good batting form, having struck 95 off 106 deliveries against Australia in Sri Lanka's first warm-up encounter. He didn't play the second practice match against New Zealand.
In the run-up to the tournament, the Sri Lanka team's form has been far below par, especially after the shocking loss to minnows Scotland.
The return of veteran pacer Lasith Malinga, whose unorthodox, slingshot action makes him one of the most difficult bowlers to face in world cricket, seems to be the only boost for the Sri Lankans.
On the other hand, often coined as the 'chokers', the South African side will be entering the match with an outside advantage having hammered the islanders 5-0 at home earlier this year.
The Proteas will bank on their batting prowess, comprising the likes of skipper AB de Villiers, Quinton de Kock, Faf du Plessis and Hashim Amla, to give them a rollicking start in the tournament.
The Proteas' bowling department will be spearheaded by No.1-ranked ODI bowler Kagiso Rabada along side the likes of Keshav Maharaj, Morne Morkel, Chris Morris and veteran leg-spinner Imran Tahir, who can be a lethal weapon in the middle overs.
South Africa: AB de Villiers (Captain), Hashim Amla, Quinton de Kock (wicketkeeper), Faf du Plessis, J.P. Duminy, David Miller, Chris Morris, Wayne Parnell, Andile Phehlukwayo, Kagiso Rabada, Imran Tahir, Dwaine Pretorius, Keshav Maharaj, Farhaan Behardien, Morne Morkel.
Sri Lanka: Angelo Mathews (Captain), Upul Tharanga , Niroshan Dickwella (wicketkeeper), Kusal Perera, Kusal Mendis, Chamara Kapugedera, Asela Gunaratne, Dinesh Chandimal (wicketkeeper), Lasith Malinga, Suranga Lakmal, Nuwan Pradeep, Nuwan Kulasekera, Thisara Perera, Lakshan Sandakan, Seekkuge Prasanna.
One of our top wins says Angelo Mathews after victory against India
CT 2017: South Africa fancy chances against Sri Lanka
We are happy to enter the tournament as underdogs: Angelo Mathews
IPL auction, 2017 - List of players up for grabs
3rd Test: South Africa won by an innings and 118 runs
South Africa won second test by 282 runs against SL
2nd Test: South Africa 297/6, Day 1 (STUMPS)
Preview: Sri Lanka vs South Africa (2nd Test)
Dambulla ODI: Australia won by 6 wickets
Colombo Test: Sri Lanka won by 163 Runs