Background: Since the beginning of the coronavirus disease 2019 (COVID-19) outbreak, dynamic mutations in the receptor-binding domain (RBD) in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have altered the pathogenicity of the variants of the virus circulating in Indonesia. This research analyzes the mutation trend in various RBD samples from Indonesia published in the Global Initiative on Sharing All Influenza Data (GISAID) database using genomic profiling. Method: Patients in Indonesia infected with SARS-CoV-2, whose samples have been published in genomic databases, were selected for this research. The collected data were processed for analysis following several bioinformatics protocols: visualization into phylogenetic trees, 3D rendering, and the assessment of mutational impact. Results: In Indonesia, there are 25 unique SARS-CoV-2 clades and 318 unique SARS-CoV-2 RBD mutations from the earliest COVID-19 sample to samples collected in 2022, with T478K being the most prevalent RBD mutation and 22B being the most abundant clade. The Omicron variant has a lower docking score, higher protein destabilization, and higher K_D than the Delta variant and the original virus. Conclusions: The study findings reveal a decreasing trend in virus pathogenicity as a potential trade-off to increase transmissibility via mutations in RBD over the years.