The purpose of the present study was to formulate and evaluate venlafaxine loaded bio-flexi film for effective treatment of depression. For the preparation of bio-flexi film biomaterial was isolated from fruits of Luffa acutangula (L.) Roxb. (Cucurbitaceae) by an economic method. The biomaterial recovered from the concentrate was subjected for various physicochemical properties like color, solubility, color changing point and chemical test. Bio-flexi films were prepared by modified solvent evaporation method in different batches with variable drug/biomaterial ratio. Prepared batches were subjected for various evaluation studies like thickness, folding endurance, in vitro and in vivo drug release. Bio-flexi films were capable of releasing the drug in a slow sustained manner. From the present investigation, it may be concluded that biomaterial isolated from fruits of L. acutangula used in the preparation of bio-flexi film exhibit promising inbuilt mucoadhesivity for delivering venlafaxine at a controlled rate. So it can serve as a powerful natural mucoadhesant. It may significantly improve the ability to cross blood-brain barrier and serve as an effective tool to treat Depression disease.