The emergence of SARS-CoV-2 and its rapid global spread underscores the urgent need for novel therapeutic strategies. This study investigates the antiviral potential of Allium sativum (garlic) extracts against SARS-CoV-2, focusing on disruption of the spike protein’s receptor-binding domain (RBD) interaction with angiotensin-converting enzyme 2 (ACE2), a critical step in viral entry. Two garlic cultivars (Tigre and Fermín) were processed via oven-drying or freeze-drying, followed by maceration with CH₂Cl₂/MeOH (1:1) and fractionation with liquid–liquid partition. ELISA immunoassays revealed that freeze-dried Tigre (TL) extracts had the highest inhibitory activity (42.16% at 0.1 µg/mL), with its aqueous fraction achieving 57.26% inhibition at 0.01 µg/mL. Chemical profiling via GC-MS found sulfur and other types of compounds. Molecular docking identified three garlic TL-derived aqueous fraction compounds with strong binding affinities (ΔG = −7.5 to −6.9 kcal/mol) to the RBD-ACE2 interface. Furthermore, ADME in silico analysis highlighted one of them (L17) as the main candidate, having high gastrointestinal absorption, blood–brain barrier permeability, and compliance with drug-likeness criteria. These findings underscore garlic-derived compounds as promising inhibitors of SARS-CoV-2 entry, calling for further preclinical validation. The study integrates experimental and computational approaches to advance natural product-based antiviral discovery, emphasizing the need for standardized formulations to address therapeutic variability across viral variants.