Acyclovir is an established antiviral agent. The global emergence of the coronavirus disease 2019 (COVID-19) pandemic brought forth the necessity to investigate potential therapeutic attributes of existing drugs, including acyclovir, to combat this novel virus. The primary focus of this research was to assess the theoretical bioactivities of acyclovir derivatives and to evaluate their molecular docking capacities, thereby determining their prospective application in treating COVID-19. A set of 22 ligand molecules derived from acyclovir were carefully selected for this study. Using the one-click docking technique, these derivatives underwent molecular interactions with specific proteins sourced from the Protein Data Bank, identified by IDs 1R4L, 1S49, 1AJ6, and 1PVG. The molecular docking analysis revealed that acyclovir derivatives no. 3, 5, 8, and 14 displayed the highest docking scores and could be potential candidates as therapeutic agents against COVID-19 based on these scores. Further experimental validations are essential to establish their efficacy in clinical settings.