Infection and entry of SARS-CoV-2 into host cells are initiated by the binding of the virus’s Spike protein to the host cell’s ACE2 receptor making it an essential therapeutic target for antiviral drug strategies. Our primary aim was to discover molecules with antiviral activity against two concerning variants of SARS-CoV-2, B.1.1.529 and BA.2, and mitigate the risk of their re-emergence. Molecular docking played a major role in this context, as it is faster and more cost-effective than experimental methods. We involved a virtual in silico molecular docking screening of 851 molecules from the South African Natural Compounds Database (SANCDB) against the Omicron variants B.1.1.529 and it’s sub-variant BA.2. Five ligands with anti-SARS-CoV-2 effects were identified for each protein based on docking scores. Promising candidates for the B.1.1.529 variant included alpha-amyrin acetate, [alpha]-Glutinol, Sodwanone Q, Kraussianone 4, and Parviflorone F. For the BA.2 sub-variant, successful molecules were Kraussianone 4, Marchantin C, Marchantin H, Sodwanone Q, and Limonin. To confirm their therapeutic potential, further studies involving molecular dynamics, in vitro, and in vivo testing are essential. Building on this exclusive in silico study could enhance the safety and efficacy of these compounds by combining them with existing treatments like remdesivir or monoclonal antibodies. Expanding this framework to investigate other highly mutable pathogens is a key future perspective aimed at strengthening public health defenses and contributing to pandemic preparedness.