Surveillance of genetic diversity of the SARS-CoV-2 is extremely important to detect the emergence of more infectious and deadly strains of the virus. In this study, we evaluated mutational events in the SARS-CoV-2 genomes through whole genome sequencing. The samples were collected from COVID-19 patients in different major cities of Pakistan during the four waves of the pandemic (May 2020 to July 2021) and subjected to whole genome sequencing. Using in silico and machine learning tools, the viral mutational events were analyzed, and variants of concern and of interest were identified during each of the four waves. The overall mutation frequency (mutations per genome) increased during the course of the pandemic from 12.19 to 23.63, 31.03, and 41.22 in the first, second, third, and fourth waves, respectively. We determined that the viral strains rose to higher frequencies in local transmission. The first wave had three most common strains B.1.36, B.1.160, and B.1.255, the second wave comprised B.1.36 and B.1.247 strains, the third wave had B.1.1.7 (Alpha variant) and B.1.36 strains, and the fourth waves comprised B.1.617.2 (Delta). Intriguingly, the B.1.36 variants were found in all the waves of the infection indicating their survival fitness. Through phylogenetic analysis, the probable routes of transmission of various strains in the country were determined. Collectively, our study provided an insight into the evolution of SARS-CoV-2 lineages in the spatiotemporal local transmission during different waves of the pandemic, which aided the state institutions in implementing adequate preventive measures.