Ronaldo shrugged off a tumultuous week which saw him dramatically leave Manchester United to bury a second-half penalty to set Portugal on their way to victory.
Andre Ayew equalised for Ghana shortly afterwards but Portugal took a 3-1 lead with goals from Joao Felix and Rafael Leao. Osman Bukari scored a late consolation for Ghana.
Cristiano Ronaldo, who appeared in his fifth World Cup, spearheaded Portugal's attack against Ghana alongside Joao Felix in their opening Group H match on Thursday.
Ronaldo left Manchester United this week in an acrimonious split after he said he felt betrayed by the club, but his coach and team mates have said the upheaval was having no impact on Portugal's preparations for their campaign in Qatar.
Portugal coach Fernando Santos partnered Ronaldo with Atletico Madrid's Felix in attack while Danilo Pereira joined Ruben Dias in the centre of defence. In midfield, Santos chose an attacking formation with only Ruben Neves as an anchor.
Ghana manager Otto Addo went for three central defenders in a bid to thwart Portugal and entrusted former Spain international Inaki Williams to lead his attack.
Teams
Portugal: Diogo Costa, Joao Cancelo, Danilo Pereira, Ruben Dias, Raphael Guerreiro, Ruben Neves, Bernardo Silva, Bruno Fernandes, Otavio, Joao Felix, Cristiano Ronaldo.
Ghana: Lawrence Ati-Zigi, Abdul-Rahman Baba, Daniel Amartey, Alexander Djiku, Mohammed Salisu, Alidu Seidu, Thomas Partey, Salis Abdul Samed, Mohammed Kudus, Andre Ayew, Inaki Williams
