<p>This paper advances an explanatory account of major depressive disorder (MDD) that locates its core pathology not in affective dysregulation or maladaptive belief content, but in a systematic impairment of abductive inference—the capacity to generate, evaluate, and revise explanatory hypotheses about oneself and the world. It first identifies a structural limitation of symptom-based psychiatric classifications such as the DSM, which secure descriptive reliability while leaving the unity of depressive phenomena theoretically unaccounted for. Drawing on Charles Sanders Peirce’s conception of abduction, the paper argues that the stable co-occurrence of depressive symptoms reflects a collapse of abductive capacity rather than a mere aggregation of independent deficits. A distinction is introduced between subjective abduction, understood as the subject’s action-mediated hypothesis testing, and objective abduction, understood as the theorist’s explanatory unification of depressive phenomena. Within this framework, depression is characterized by restricted hypothesis generation, biased inference to the best explanation, and impaired action-based model updating. The account is further integrated with active inference—an extension of predictive processing that treats action as an integral part of hypothesis testing—providing the mechanistic realization of abductive reasoning. On this view, hopelessness, motivational paralysis, and rigid self-narratives emerge from a disrupted abductive–active-inferential cycle. Reconceptualizing depression as a disorder of abductive agency restores explanatory unity to depressive psychopathology.</p>