The Black Stars amassed 13 points to top Group C followed by Sudan with 12 points while South Africa had 10 points. Sao Tome recorded no points.
Sao Tome & Principe started the game a very confident side as they attacked the Black Stars goal area and looked the more dangerous side in the opening 10 minutes.
But it was the Black Stars who took an early lead in the 13th minute through Nicholas Opoku who headed in from close range after a superb corner-kick from Mohammed Kudus.
Sao Tome nearly responded in quick fashion but a well-struck free-kick from Dos Anjos narrowly went off the cross bar.
The Black Stars were largely in control of the game with exquisite passing in the midfield area with the likes of Thomas Partey, Kudus Mohammed, and Mubarak Wakaso all in action.
Djibouti Referee Souleiman Djama awarded Ghana a penalty in the 31st minute after Jordan Ayew was brought down in the penalty box.
The Crystal Palace marksman stepped up and struck home from 12 yards to give Black Stars the cushion lead.
The pressure on True Patriots of Sao Tome & Principe was relentless and Nicholas Opoku nearly grabbed his second the day from another header that missed the target.
Kudus Mohammed who scored in Ghana’s last game against South Africa nearly scored Ghana’s third in the late stages of the first half but Sao Tome & Principe goalkeeper Cravid De Almeida pulled up a brilliant save to deny the Ajax midfielder.
The first half ended with Ghana in cruise control of the match with their two-goal lead.
The Black Stars started the second half on the front foot as they searched for more goals against an opposition who had conceded the most number goals in the group.
Substitute Gladson Awako had a glorious opportunity to score his debut goal for the Black Stars in the 53rd minute but skied his effort from close range.
Baba Rahman grabbed Ghana’s third goal in the 60th minute after he struck in from close after he was beautifully teed up by Mohammed Kudus.
Sao Tome & Principe had little to offer in the final third with Ghana goalkeeper Razak Abalora largely on holiday.
The Black Stars bossed the game with coach C.K Akunnor giving some new players including Kwesi Okyere and Moro Ibrahim their debut.
Sao Tome and Principe pulled a goal back through substitute Jokceleny Fernandes Carvalho after a horrific mistake by Black Stars goalkeeper Razak Abalora who failed to clear his lines in the late stages of the game.
It was a nervy finish for the Black Stars but they were able to hold on to secure maximum points.
Black Stars Starting Line-Up: Razak Abalora (GK), Benson Annan, Baba Abdul Rahman (Kwesi Okyere), Ismail Ganiyu, Nicholas Opoku, Thomas Partey, Mubarak Wakaso (Justice Blay), Osman Bukari(Gladson Awako), Jordan Ayew (Moro Ibrahim), Andre Ayew, Mohammed Kudus
Sao Tome and Principe Starting Line-Up: Cravid De Almeida (GK), Ivan Dias Mendes, Edley Perrera, Jardel Nazare, Joel Das Neves, Soarez De Cruz, Edmilson Di Lima, Luis Leal Dos Anjos, Jose Carlos Da Costa, Ricardo Cardozo, Correa Nilson.