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The rapid genetic evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 (COVID-19) pandemic has greatly challenged public health authorities worldwide, including in Mauritania. Despite the presence of the virus in Mauritania, only one study described its genomic variation during the course of the epidemic. The purpose of the present study was to document the genomic pattern of SARS-CoV-2 variants from clinical isolates during the COVID-19 outbreak in Mauritania, from September to November 2021. The whole genomes from 54 SARS-CoV-2 strains detected in nasopharyngeal swabs with a cycle threshold value ≤ 30 were successfully sequenced using next-generation sequencing (NGS) and the Illumina protocol. The mean genome coverage (±standard deviation) was 96.8% (±3.7). The most commonly identified clade was 21J (57.4%), followed by 21D (16.7%), 20A (11.1%), and 20B (9.2%). At the level of lineages, the majority of the samples were Delta variants with the sub-lineage AY.34 (or B.1.617.2.34). Among the 54 SARS-CoV-2 isolates that were successfully sequenced, 33 (61.1%) came from vaccinated individuals, and 21 (38.9%) were from unvaccinated individuals. Several SARS-CoV-2 variants were present in Mauritania between September and November 2021. As Mauritania, like many West African countries, is resource-limited regarding viral genome sequencing facilities, establishment of mutualized sub-regional sequencing platforms will be necessary to ensure continuous monitoring of mutations in viral genomes and track potential reduction in COVID-19 vaccine efficacy, increased transmissibility, and disease severity.