Malaria is a significant global health threat, with Plasmodium falciparum identified as the most pathogenic species. The pathogen also contributes to elevated mortality and morbidity rates, especially in sub-Saharan Africa. On the other hand, the rise of drug-resistant strains, particularly to artemisinin-based combination therapies (ACTs) is the major concern that necessitates the identification of new therapeutic targets and lead compounds. The heme detoxification protein (HDP) assists the Plasmodium falciparum parasite in converting toxic heme released during hemoglobin digestion into inert, nontoxic crystalline hemozoin. Consequently, the inhibition of HDP presents a novel strategy for the design of potent anti-malarial drugs. This study presents the foundational application of an integrated computational approach to screen and validate natural inhibitors of HDP, identifying tetrandrine, a bis-benzyl-isoquinoline alkaloid, which has also been reported by in-vitro studies to demonstrate significant anti-malarial activity. However, due to the unavailability of the crystal structure of HDP protein, it was modeled using both the AlphaFold and SWISS-MODEL platforms. The model generated with the AlphaFold demonstrated stability suggested by the stereochemical examination, the Ramachandran geometry assessment, and robust per-residue confidence score evaluations. Docking analysis revealed that Tetrandrine exhibited the highest affinity for the HDP active site (-13.0 kJ/mol), surpassing Bisnordihydrotoxiferine (-10.2 kJ/mol), Neferine (-9.01 kJ/mol), and Oxytetracycline (-10.9 kJ/mol). Whereas, Tetrandrine was found to have stabilizing interactions with His122, His172, His175, and His197. The 100 ns molecular dynamics (MD) simulations confirmed the stability of the HDP ligand (tetrandrine) complex. The RMSD, RMSF, radius of gyration (Rg), and solvent-accessible surface area (SASA) indicated the complex formation affecting the adaptability and conformational stability of the protein. The Principal Component Analysis (PCA) and Dynamic Cross Correlation Matrix (DCCM) demonstrated that ligand binding significantly changed the cross-correlation movements of the domains and regulatory flexibility, affecting long-range allosteric communication of the protein as a whole. The MM-PBSA free energy calculations supported the docking findings, as Tetrandrine was found to have higher binding energy, (-30 kcal/mol), suggesting the thermodynamically favorable binding complex.