The World Health Organization (WHO) recorded an estimated 263 million malaria cases globally in 2023, leading to about 597,000 mortalities. Most of this burden occurred in the WHO African Region, which accounted for approximately 94% of cases and 95% of malaria-related deaths. Artemisinin-based combination therapies (ACTs) remain the mainstay of malaria treatment globally; however, the emergence of Plasmodium falciparum resistance compromises their sustained efficacy. Although mutations in the Plasmodium falciparum Kelch 13 (Pfk13) propeller domain are largely proven to be markers of partial artemisinin resistance, greater focus has turned to Plasmodium falciparum Adenosine Triphosphatase 6 (PfATPase6) as a potential supplementary determinant. This review compiled evidence from published articles between 2015 and 2025, sourced from Google Scholar, PubMed, ProQuest, and ScienceDirect, with a focus on PfATPase6 polymorphisms, their distribution, functional role, detection techniques, and implications for malaria prevention. Notable nonsynonymous single-nucleotide polymorphisms (SNPs) such as E431K, S769N, A623E, S769M, and M699V have been reported spanning Asia, the Americas, and Africa. Several studies reveal a correlation with decreased in vitro susceptibility or enhanced artemether Half Maximal Inhibitory Concentration (IC₅₀), although findings are inconsistent due to interrelated resistance markers, environmental differences, and deviations in methodology. Recent improvements in molecular monitoring techniques, like next-generation sequencing, high-resolution melting analysis, and advanced real-time polymerase chain reaction (PCR) techniques, have broadened the ability to detect uncommon variants and have reinforced surveillance systems. Despite inconsistency in findings, there is evidence that PfATPase6 reduces sensitivity to artemisinin; therefore, it should be taken into consideration in resistance surveillance schemes. It is recommended to incorporate PfATPase6 genotyping alongside Pfk13 surveillance and treatment efficacy studies to offer more insights into the emergence of resistance. These approaches are vital to expound the underexplored role of the PfATPase6 in resistance patterns and encourage the sustainability of antimalarial drugs.