The third wave of the global health crisis attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus reached Colombia in March 2021. Over the following 6 months, it was interpolated by manifestations of popular disapproval to the actual political regime-with multiple protests sprouting throughout the country. Large social gatherings seeded novel coronavirus disease 2019 (COVID-19) variants in big cities and propagated their facile spread, leading to increased rates of hospitalizations and deaths.In this article, we evaluate the effective reproduction number (Rt) dynamics of SARS-CoV-2 in Cali, Colombia, between 4 April 2021 and 31 July 2021 based on the analysis of 228 genomes.Our results showed clear contrast in Rt values between the period of frequent protests (Rt > 1), and the preceding and following months (Rt < 1). Genomic analyses revealed 16 circulating SARS-CoV-2 lineages during the initial period-including variants of concern (VOCs) (Alpha, Gamma, and Delta) and variants of interest (VOIs) (Lambda and Mu). Furthermore, we noticed the Mu variant dominating the COVID-19 distribution schema as the months progressed. We identified four principal clusters through phylogenomic analyses-each one of potentially independent introduction to the city. Two of these were associated with the Mu variant, one associated with the Gamma variant, and one with the Lambda variant.Our results chronicle the impact of large group assemblies on the epidemiology of COVID-19 during this intersection of political turmoil and sanitary crisis in Cali, Colombia. We emphasize upon the effects of limited biosecurity strategies (which had characterized this time period), on the spread of highly virulent strains throughout Cali and greater Colombia.