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Plasmodium parasites, the causal agents of malaria, are eukaryotic organisms that obligately undergo sexual recombination within mosquitoes. In low transmission settings, parasites recombine with themselves, and the clonal lineage is propagated rather than broken up by outcrossing. We investigated whether stochastic/neutral factors drive the persistence and abundance of Plasmodium falciparum clonal lineages in Guyana, a country with relatively low malaria transmission, but the only setting in the Americas in which an important artemisinin resistance mutation (pfk13 C580Y) has been observed. We performed whole genome sequencing on 1,727 Plasmodium falciparum samples collected from infected patients across a five-year period (2016–2021). We characterized the relatedness between each pair of monoclonal infections (n = 1,409) through estimation of identity-by-descent (IBD) and also typed each sample for known or candidate drug resistance mutations. A total of 160 multi-isolate clones (mean IBD ≥ 0.90) were circulating in Guyana during the study period, comprising 13 highly related clusters (mean IBD ≥ 0.40). In the five-year study period, we observed a decrease in frequency of a mutation associated with artemisinin partner drug (piperaquine) resistance (pfcrt C350R) and limited co-occurence of pfcrt C350R with duplications of plasmepsin 2/3, an epistatic interaction associated with piperaquine resistance. We additionally observed 61 nonsynonymous substitutions that increased markedly in frequency over the study period as well as a novel pfk13 mutation (G718S). However, P. falciparum clonal dynamics in Guyana appear to be largely driven by stochastic factors, in contrast to other geographic regions, given that clones carrying drug resistance polymorphisms do not demonstrate enhanced persistence or higher abundance than clones carrying polymorphisms of comparable frequency that are unrelated to resistance. The use of multiple artemisinin combination therapies in Guyana may have contributed to the disappearance of the pfk13 C580Y mutation. Author summary: Malaria is caused by eukaryotic Plasmodium parasites, which undergo sexual recombination within mosquitoes. In settings with low transmission, such as Guyana, these parasites often recombine with themselves, leading to the propagation of identical clones. We explored the population genomics of Plasmodium falciparum malaria parasites in Guyana over five years to characterize clonal transmission dynamics and understand whether they were influenced by local drug resistance mutations under strong selection, including pfk13 C580Y, which confers resistance to artemisinin, and pfcrt C350R, which confers resistance to piperaquine. Based on whole genome sequencing results from 1,409 monoclonal (single-strain) samples, we identified 160 multi-isolate clones, in which all parasites share at least 90% of their genomes through recent common ancestry. We observed a decrease in frequency of the pfcrt C350R mutation, as well as the disappearance of pfk13 C580Y. Our findings contrast with the deterministic rise of drug resistance mutations observed in other geographic regions, sometimes associated with clonality. The simultaneous use of at least two different artemisinin combination therapies may have prevented the spread of an artemisinin-resistant clone in Guyana, suggesting a strategy for resistance management in other geographic regions. [ABSTRACT FROM AUTHOR]