Background:  The emergency of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) variants has led to COVID-19 worldwide with substantial social and economic consequences. SARS CoV-2 S-glycoproteins are involved in viral entry to human cells. They are naturally the main target of host immune responses, and most vaccine designs are based on them. SARS-CoV-2 variants are categorized as variants of interest (VOI) or variants of concern (VOC) because they are deadly and highly transmissible, causing illness by overcoming the host immune system. Material and Methods: The COVID-19 patients' samples were isolated for genome sequencing to identify the mutations that alter the viral genotypic traits. Genome annotation and phylogenetic analysis were performed using MEGA 7.0. Results: Phylogenetic analysis revealed that the omicron variant of concern and sub-variants XBB, XBB.2.6, BQ.1, and BQ.1.1 are the most prevalent variants in Lusaka, Zambia. Analysis of the translated protein sequences in this study revealed D614G mutation in all the sequences. This mutation has previously been implicated in viral transmission, increasing the infectivity, replication efficacy, stability of virions, and virulence in its human host.  Conclusion: Analysis of the SARS-CoV-2 genome provided crucial information on the variant and its source as it spreads in Lusaka from person to person. This research has a huge potential in genomic epidemiology, where genomic surveillance is employed to detect new mutations or SARS-CoV-2 variants, which can help the virus to spread rapidly, increase disease severity, or even evade vaccine-induced immunity.