Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as HLA-B*57:01, HLA-B*15:02, and HLA-B*58:01, are known risk factors for adverse reactions induced by multiple drugs. However, the structural basis underlying most HLA-associated adverse events remains poorly understood. This review summarizes the application of molecular docking to reveal the mechanisms of IDR-related HLA associations, covering studies using this technique to examine drug-HLA binding pockets and identify key binding residues. We provide a comprehensive overview of risk HLA alleles associated with IDRs, followed by a discussion of the utility and limitations of commonly used molecular docking tools in simulating complex molecular interactions within the HLA binding pocket.Through examples, including the binding of abacavir to HLA-B*57:01, carbamazepine to HLA-B*15:02, and allopurinol to HLA-B*58:01, we demonstrate how docking analyses can provide insights into the drug and HLA allele-specificity of adverse events. Furthermore, the use of molecular docking to screen drugs with unknown IDR liability is examined, targeting either multiple HLA variants or a single specific variant. Despite multiple challenges, molecular docking presents a promising toolkit for investigating drug-HLA interactions and understanding IDR mechanisms, with significant implications for preemptive HLA typing and safer drug development.