Victory leaves the Chipolopolo unmoved in Group K, but level on four points with both Mozambique and Djurtus ahead of the return fixture in Bissau later this week.
The hosts dominated most of the clash and opened the scoring through Stoppila Sunzu in the 18th minute.
Orlando Pirates forward Justin Shonga made it two goals in two games as he doubled the home sides lead seven minutes following the break, as Zambia threatened to run away with it.
Zambia, though, missed a catalogue of chances in the closing stages with Lubambo Musonda and second-half substitute Patson Daka squandering gilt-edged opportunists for the hosts as they made life unnecessarily difficult for themselves.
Musonda particularly at fault with midfielder blazing his attempt over the crossbar when it looked easier to score, following good work by Augustine Mulenga down the left flank.
Zambia almost paid the ultimate price as Frédéric Mendy pulled a goal back for the visitors in the 80th minute to make for a nervy end to the match.
Toni Silva hustled and harried Mamelodi Sundowns teammate and Zambia captain Kennedy Mweene, who’s costly error was pounced on by Mendy with the forward on hand to convert from close range.
Musonda had another chance four minutes later to restore Zambia’s lead, but was unlucky to see his header canon off the woodwork.
Notoriously strong finishers, as Zambia can attest, Guinea Bissau pushed forward in search of the equalizer, but lucky for the hosts and particularly Mweene, it would not be forthcoming.
The reverse fixture will take place at the Estádio 24 de Setembro in Bissau on Sunday.