Background <p>Malaria remains a significant public health challenge in Nigeria, accounting for a substantial proportion of global malaria cases and deaths. Although artemisinin-based combination therapies (ACTs) are the recommended first-line treatments, resistance to antimalarial drugs continues to threaten malaria control efforts. This systematic review provides an overview of the molecular surveillance of antimalarial drug resistance in Nigeria, aiming to identify prevalent resistance markers and inform future research and policy directions.</p> Methods <p>A systematic search was conducted using databases including PubMed, ScienceDirect, Ovid and Scopus. Studies published from 2010 to 2024 and focused on key resistance markers such as <i>Pfcrt</i>, <i>Pfmdr</i>, <i>Pfdhfr</i>, <i>Pfdhps</i>, and <i>Pfk13</i> genes were included.</p> Results <p>A total of 26 studies met the inclusion criteria, revealing a high overall prevalence of mutations associated with resistance to chloroquine and sulfadoxine-pyrimethamine, particularly in <i>Pfcrt</i> and <i>Pfdhfr</i> genes. Although mutations associated with artemisinin resistance in the <i>Pfk13</i> gene were less common, their presence warrants attention for future surveillance. Within this overall pattern, regional disparities were evident, with generally lower <i>Pfcrt</i> prevalence in northern Nigeria compared to the south, though levels varied across locations and time periods.</p> Conclusion <p>Regional variability in CQ resistance mutations has been observed across Nigeria, with lower prevalence in some northern states but persistence in others. CQ may be reconsidered as an alternative to ACTs only in areas where resistance remains consistently low, contingent upon clinical trials confirming efficacy and safety, and accompanied by molecular surveillance to guide targeted policy decisions.</p>