Apoptosis is an implicit cell suicide pathway which plays a pivotal role in both normal and pathophysiological conditions. The intrinsic apoptotic pathway is tightly regulated by BCL-2 family proteins. In order to trigger apoptosis in cancerous cells, several chemotherapeutic agents were being used as anticancer agents, but still novel compounds are explored for enhanced chemoprevention. The computational approaches towards screening of active compounds made easier to ascertain their possible mechanism of action before experimental trials. Orientin, the C-glycoside of luteolin (Luteolin-8-C-glucoside) is known to exert the promising cytotoxic effect in human cancer cell lines. However, the target specific mechanism of Orientin has been not elucidated. The present study dealt with Glide XP and QPLD approach to substantiate the binding capacity of Orientin with that of apoptotic proteins which regulate the homeostasis. Further, the binding free energy calculation and pharmacokinetic properties also predicted. Overall, experimental findings suggested that Orientin has the inhibitory activity against anti-apoptotic proteins and exhibited the drug like characteristics. The insights obtained from the present work can be facilitated to carry out the experimental analysis to verify the anticancer effect of Orientin.