The continuously emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have made the global coronavirus disease 2019 (COVID-19) pandemic unpredictable. Since the beginning of the pandemic, densely populated South and Southeast Asia have suffered great losses due to multiple COVID-19 surges because of vaccine and other medical resource shortages. Therefore, it is crucial to closely monitor the SARS-CoV-2 epidemic and to understand the evolutionary and transmission characteristics of SARS-CoV-2 in these regions. Here, we document the evolution of epidemic strains in the Philippines, Pakistan, and Malaysia from late 2021 to early 2022. Our results confirmed the circulation of at least five SARS-CoV-2 genotypes in these countries in January 2022, when Omicron BA.2, with a detection rate of 69.11%, replaced Delta B.1.617 as the dominant strain. Single-nucleotide polymorphism analysis indicated the distinct evolutionary directions of the Omicron and Delta isolates, withS,Nsp1, andNsp6genes potentially playing a significant role in the host adaptation of the Omicron strain. These findings are able to provide insights for predicting the evolutionary direction of SARS-CoV-2 in terms of variant competition, developing multi-part vaccines, and to support the evaluation and adjustment of current surveillance, prevention, and control strategies in South and Southeast Asia.