Abdu Maikaba’s Flying Eagles took control early, with Olayemi Ayinla opening the scoring in the sixth minute.
The Black Satellites responded strongly by restoring parity through Mohammed Zaidan in the 23rd minute.
Nigeria regained the lead when Oraro Isaac struck on the half-hour mark, before Muiz Adeleke extended the advantage five minutes later to put the holders 3-1 ahead at the break.
Ghana refused to surrender and reduced the deficit shortly after the restart, with Kelvin Nkrumah converting from the penalty spot.
However, Nigeria remained composed, and Adeleke sealed the victory with his second goal, calmly converting a late penalty.
The result gives Nigeria a perfect start as they pursue a third consecutive WAFU B U-20 title. They face Togo on Thursday.