While a complete understanding of organic semiconductor (OSC) design principles remains elusive, computational methods─ranging from techniques based in classical and quantum mechanics to more recent data-enabled models─can complement experimental observations and provide deep physicochemical insights into OSC structure-processing-property relationships, offering new capabilities for in silico OSC discovery and design. In this Review, we trace the evolution of these computational methods and their application to OSCs, beginning with early quantum-chemical methods to investigate resonance in benzene and building to recent machine-learning (ML) techniques and their application to ever more sophisticated OSC scientific and engineering challenges. Along the way, we highlight the limitations of the methods and how sophisticated physical and mathematical frameworks have been created to overcome those limitations. We illustrate applications of these methods to a range of specific challenges in OSCs derived from π-conjugated polymers and molecules, including predicting charge-carrier transport, modeling chain conformations and bulk morphology, estimating thermomechanical properties, and describing phonons and thermal transport, to name a few. Through these examples, we demonstrate how advances in computational methods accelerate the deployment of OSCsin wide-ranging technologies, such as organic photovoltaics (OPVs), organic light-emitting diodes (OLEDs), organic thermoelectrics, organic batteries, and organic (bio)sensors. We conclude by providing an outlook for the future development of computational techniques to discover and assess the properties of high-performing OSCs with greater accuracy.