Captain William Troost-Ekong broke the deadlock in the 55th minute from the penalty spot, before substitute Akor Adams made it 2–0 in the 80th minute.
Lesotho responded quickly as Hlompho Kalake found the net in the 83rd minute, but Nigeria stood their ground to claim a crucial three points.
The victory leaves the Super Eagles third in CAF Group C with 14 points — one behind South Africa and three behind leaders Benin. Nigeria will host Benin Republic in Uyo on Tuesday in what could be a decisive clash for their World Cup dreams.