Lipase, an acute pancreatic marker protein, is a digestive enzyme that breaks down triacylglycerol into glycerol. Due to the presence of bile salt, pancreatic lipase cannot function without colipase. Fluctuation of lipase level causes acute pancreatitis, cystic fibrosis, and Crohn’s disease. So, it is essential to study about the molecular and residual basis of lipase and co-lipase interactions. In this study, amino acid sequences of human lipase and colipase protein were extracted. Manifold molecular modeling was performed to select the best 3D structure of lipase and colipase. Active sites in lipase were observed to participate in interaction with colipase. Spontaneity of interaction and net area for solvent accessibility were evaluated. Conformational shifts in the proteins before and after optimization were observed. Interactions after protein–protein docking simulations show that all three aromatic amino acids from lipase exhibited aromatic interactions. Charged residues, Arg and Lys, were seen to interact with lipase. Among other hydrophobic interactions, 54% of interactions were undergone by Ile and Leu. Only, tyrosine residues formed the aromatic interactions from colipase. This study creates a new path for future research on human lipase and colipase for competent drug discovery as without an exploration of the residue level, it remains incomplete.