MM-PBSA binding free energy calculations consistently suggested a strong and stable interaction between NPC1L1-ergosterol (-27.61 ± 3.72 kcal/mol), comparable to that of NPC1L1-ezetimibe (-19.42 ± 4.87 kcal/mol) and NPC1L1-cholesterol (-32.53 ± 3.71 kcal/mol) complex.<h4>Conclusion</h4>Our computational modelling studies suggested that ergosterol forms energetically favourable interactions with NPC1L1, hinting at its potential as a candidate for hypercholesterolemia and CVD management. The gene discussed is NPC1L1; the disease is familial hypercholesterolemia.