The population structure of Staphylococcus aureus is changing globally but the situation regarding dominant clones in sub-Saharan Africa is not clear. We therefore assessed changes in the population structure of clinical S. aureus isolates obtained in 2007 (n = 75) and 2012 (n = 75) from Northeastern Nigeria. A reduction in resistance to penicillin, gentamicin, erythromycin and clindamycin was observed in 2012. A decrease of methicillin resistance rates (13·3% to 8·0%) was associated with the decline of the ST241 MRSA clone. The proportion of Panton-Valentine leukocidin (PVL)-positive isolates also decreased from 65·3% to 44%, and was linked with the emergence of PVL-negative ST601 clone in 2012. The significant decline in antibiotic resistance in the study area is in contrast to the worldwide trend of increasing resistance rates.