Background: Malaria remains highly endemic in Cameroon. The rapid emergence and spread of drug resistance was responsible for the change from monotherapies to artemisinin-based combinations. This systematic review and metaanalysis aimed to determine the prevalence and distribution of Plasmodium falciparum drug resistance markers within an evolving efcacy of anti-malarial drugs in Cameroon from January 1998 to August 2020. Methods: The PRISMA-P and PRISMA statements were adopted in the inclusion of studies on single nucleotide polymorphisms (SNPs) of P. falciparum anti-malarial drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfatp6, Pfcytb and Pfk13). The heterogeneity of the included studies was evaluated using the Cochran’s Q and I2 statistics. The random efects model was used as standard in the determination of heterogeneity between studies. Results: Out of the 902 records screened, 48 studies were included in this aggregated meta-analysis of molecular data. A total of 18,706 SNPs of the anti-malarial drug resistance genes were genotyped from 47,382 samples which yielded a pooled prevalence of 35.4% (95% CI 29.1–42.3%). Between 1998 and 2020, there was signifcant decline (P<0.0001 for all) in key mutants including Pfcrt 76 T (79.9%-43.0%), Pfmdr1 86Y (82.7%-30.5%), Pfdhfr 51I (72.2%66.9%), Pfdhfr 59R (76.5%-67.8%), Pfdhfr 108 N (80.8%-67.6%). The only exception was Pfdhps 437G which increased over time (30.4%-46.9%, P<0.0001) and Pfdhps 540E that remained largely unchanged (0.0%-0.4%, P=0.201). Exploring mutant haplotypes, the study observed a signifcant increase in the prevalence of Pfcrt CVIET mixed quintuple haplotype from 57.1% in 1998 to 57.9% in 2020 (P<0.0001). In addition, within the same study period, there was no signifcant change in the triple Pfdhfr IRN mutant haplotype (66.2% to 67.3%, P=0.427). The Pfk13 amino acid polymorphisms associated with artemisinin resistance were not detected.