A combined experimental and analytical investigation is conducted to develop a mechanism-based general friction theory for PTFE/PEEK composite. The PTFE/PEEK composites with PTFE and PEEK volume contents ranged from 0% to 100% were fabricated; their microstructure features were examined and recorded; and their friction coefficients were determined by sliding friction experiments. From the observed microstructure features of PTFE/PEEK composite with different PTFE and PEEK volume contents and the well-recognized unique “band” morphology and sliding deformation mechanisms of the semi-crystalline PTFE, associated “apparent” sliding friction behavior is ascribed to the PTFE material in accordance with its volume content in the composite. A mechanism-based general friction theory is developed for PTFE/PEEK composite based on the associated “apparent” friction coefficient of the PTFE phase in composite. The general friction theory is validated through the excellent agreement obtained between the analytical predictions of composite friction coefficients and the comprehensive experimental results obtained from the sliding friction tests conducted in-house with a pin-on-disk tribometer, and also from those (obtained with different types of tribo-testers) reported in the literature.