A smart biosensor based on piezoelectric and semiconducting properties of Barium titanate nanoparticles (BT NPs) by means of a piezoelectric nanogenerator (PNG) is reported for the first time. An Al/BT/ITO NG (Aluminum (Al)/Barium titanate (BT)/Indium Tin Oxide (ITO) nanogenerator) was devised as a self-powered biosensor for actively detecting glucose. The piezoelectric output generated from this NG has dual functions, as both an energy source and a biosensing signal. The biomolecule alters device conductance (charge-carrier density), providing a gate potential, and can vary the local work function and band alignment due to its adsorption on the surface of BT NPs (interfacial contact effect). Here, we tailored the piezoelectric and semiconducting properties of BT NPs using glucose molecules. The glucose molecules (lewis base) on the surface of BT NPs film (lewis acid) act as a gate potential, and the field effect eventually influence the charge carrier density (electrons) of BT NPs film, which varies the screening effect of free-carriers on the piezoelectric output. The novel self-powered glucose biosensor has good selectivity (∼6-fold increase in response vs. interferents) and the approach demonstrated here can serve as a prototype for the development of next-generation smart/self-powered nanosystems for theranostic applications.