Background: An outbreak of an unknown respiratory illness caused by a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan in Hubei Province, China, in December 2019 and was referred to as coronavirus disease-2019 (COVID-19). Soon after, it was declared as a global pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 mainly infects the respiratory tract with different outcomes ranging from asymptomatic infection to severe critical illness leading to death. Different SARS-CoV-2 variants are emerging of which three have raised concerns worldwide due to their high transmissibility among populations. Objective: To study the prevalence of COVID-19 in the region of Nabatieh-South Lebanon during the past year and assess the presence of SARS-CoV-2 variants and their effect on the spread of infection during times of lockdown. Methods: In our study, 37,474 nasopharyngeal swab samples were collected and analyzed for the detection of SARS-CoV-2 virus in suspected patients attending a tertiary health care center in South Lebanon during the period between 16 March 2020 and 21 February 2021. Results: The results demonstrated a variation in the prevalence rates ranging from less than 1% during full lockdown of the country to 8.4% upon easing lockdown restrictions and reaching 27.5% after the holidays and 2021 New Year celebrations. Interestingly, a new variant(s) appeared starting January 2021 with a significant positive association between the prevalence of positive tests and the percentage of the variant(s). Conclusions: Our results indicate that the lockdown implemented by the Lebanese officials was an effective intervention to contain COVID-19 spread. Our study also showed that lifting lockdown measures during the holidays, which allowed indoor crowded gatherings to occur, caused a surge in COVID-19 cases and rise in the mortality rates nationwide. More importantly, we confirmed the presence of a highly transmissible SARS-CoV-2 variant(s) circulating in the Lebanese community from at least January 2021 onwards.