Background In malaria endemic regions, Plasmodium falciparum infection is characterized by variable genetic diversity at different settings. The parasite's various forms are found at varied frequency in different geographic areas, resulting in different levels of multiplicity of infection. This study was under taken to determine the status of P. falciparum genetic diversity and MOI in different regions of Ethiopia.Methods Relevant publications were identified from electronic databases such as; PubMed, EMBASE, Scopus, Google scholar and Google. Besides, an online search was done using the above databases for all articles published in English on genetic diversity of P.falciparum in Ethiopia. STATA software was used for data analysis. The pooled estimates were calculated using random effect model. The summary estimates were presented using forest plots and tables.Results A total of 11 studies were included in the systematic review. However, only 8, 10 and 2 studies were included for Pfmsp-1, msp-2 and glurp gene meta-analysis, respectively. However, the meta-analysis result showed that the pooled prevalence of Pfmsp-1, msp-2 and glurp gene were 84% for both msp-1/2 and 51%, respectively. The pooled prevalence of msp-1 gene was higher in Amhara region followed by Oromia region and lower in SNNPR while, for msp-2 gene the pooled prevalence was higher in Benshangul gumez region and lower in SNNPR. Among the allelic family of msp-1 and msp-2 genes, MAD20 (34%) and FC27 (44%) were the most predominant respectively.Conclusion Based on the review, there is evidence of the presence of high genetic diversity of P. falciparum parasites in Ethiopia, suggesting that malaria transmission remain high and that strengthened control efforts are needed. The approaches and methods used for investigation, confirmation and reporting of diversified parasites have similarity between studies and across regions and should use advanced molecular techniques, like microsatellite, whole genome sequence and capillary electrophoresis to assess the genetic diversity of P. falciparum for better determination of P. falciparum genetic diversity.