Abstract

Malaria remains one of the most significant public health challenges globally, with sub-Saharan Africa and particularly Nigeria, bearing a disproportionate share of the disease burden. Despite advances in vector control and the adoption of artemisinin-based combination therapies (ACTs), the rapid emergence and spread of drug-resistant Plasmodium falciparum strains threaten recent gains in malaria control. A critical yet underexplored factor accelerating this resistance evolution is the presence of polyclonal infections, wherein multiple genetically distinct parasite strains coexist within a single host. These mixed-strain infections foster within-host competition, facilitate recombination events in the mosquito vector, and increase the probability of survival for resistant clones under drug pressure. This review synthesizes current knowledge on the biological and epidemiological underpinnings of polyclonality, its role in resistance dynamics, and its unique significance in the Nigerian context, where high transmission intensity and suboptimal treatment practices amplify the problem. We highlight diagnostic limitations in detecting minority resistant clones, the clinical consequences of recrudescence and therapeutic failure, and the role of polyclonal carriers as potential super spreaders of resistant parasites. Furthermore, we examine current resistance trends in Nigeria, discuss surveillance and treatment gaps, and propose integrated strategies encompassing molecular monitoring, diagnostic improvements, optimized treatment policies including triple ACTs and vector control measures. By identifying knowledge gaps and synthesizing evidence across clinical, epidemiological, and molecular dimensions, this review underscores the urgent need for multifaceted interventions tailored to Nigeria’s malaria ecosystem. Addressing polyclonal infections in resistance management is critical to sustaining the efficacy of frontline therapies, protecting vulnerable populations, and advancing global malaria elimination goals.