Cancer as well as neurological and mental disorders are a major and increasing global health challenge with complex underlying pathomechanisms involving dysregulation of multiple molecular targets. A polypharmacological approach, which refers to the simultaneous modulation of multiple interacting targets, seems particularly promising given the complexity and multifactorial nature of such diseases. Multi-target quantitative structure–activity relationship study (MT-QSAR) was developed as a computational modeling technique that takes into account drug interactions with multiple molecular targets and as such enables the design of polypharmacological drugs. This advanced QSAR method, especially in combination with molecular docking, can provide information on key structural characteristics that are crucial for successful binding of ligand to different receptors. In this chapter, we give an overview of the application of multi-target QSAR in the discovery of novel types of therapeutics for the treatment of cancer and neurological and mental diseases that exert their effects through multiple molecular targets.