The teams have been drawn in Group A of the qualifying campaign where they will do battle with Nigeria and Sierra Leone for a place in the hat at next year's continental tournament.
Match preview
Guinea-Bissau fell to a 3-2 defeat against Angola in their last involvement on March 26 at the Estadio Municipal de Rio Maior.
Baciro Cande's men gave a good account of themselves on the day but two goals from Ary Papel and a Zini strike rendered goals in either half from Zinho Gano and Mauro Rodrigues inconsequential.
Consequently, the Djurtus still remain with only one victory from nine outings across all competitions stretching back to last October.
Coming up next is the task of taking on an opposing side who have come away empty-handed from each of the previous two meetings between the teams.
However, Thursday's hosts are without a home victory in their most recent five outings which is definitely a cause for concern heading into this one.
Sao Tome & Principe held Mauritius to a thrilling 3-3 draw to secure a 4-3 aggregate triumph in the preliminary AFCON qualifying round back in March.
Ricardo Cardoso was the hero for Adriano Eusebio's men at the National Sports Complex as he netted in both halves to force a share of the spoils.
Off the back of six consecutive defeats, the Central Africans will now seek to go three games without a defeat for the first time in over a decade.
Meanwhile, Thursday's visitors are also yet to win away from home since 2019 and now would be as good a time as any to end that dry spell on the road.
Guinea-Bissau form (all competitions):
Sao Tome & Principe form (all competitions):
Team News
Having opened his international account last time out, Guinea-Bissau's Zinho Gano will be seeking to deliver the goods for his side once again.
Twenty-one-year-old Mauro Rodrigues has been left out for the home side having struggled consistently for playing minutes at club level.
With three goals in his last two appearances, Luis Leal continues to extend his lead at the top of Sao Tome's all-time scoring charts and the 35-year-old is one to keep an eye on.
Leal is also set for a 20th national-team cap and would become just the fourth player in his nation's history to reach that milestone.
Guinea-Bissau possible starting lineup:
Gomis; Nogueira, Mane, Nanu, Cande; Cassama, Semedo, Bikel; Piqueti, Jorginho, Gano
Sao Tome & Principe possible starting lineup:
Primo; Ivonaldo, Pequeno, Soares, Oliveira; Jocy, Barbeiro, Iniesta; Leal, Cardoso, Santos