Social dysfunction plays a critical role in the development and maintenance of depression in both adolescents and adults. Interpersonal psychotherapy (IPT) and interpersonal psychotherapy for depressed adolescents (IPT-A) are effective, evidence-based, and time-limited treatments for depression that aim to mitigate depressive symptoms by strengthening an individual’s interpersonal relationships and skills. Though the efficacy of IPT/IPT-A has been well established, we are just beginning to know how biological systems are implicated in its success. In this scoping review, we examine the extant literature on biological mechanisms and predictors of IPT/IPT-A treatment efficacy. Overall, seven studies were identified that consider biological processes in the context of evaluating IPT/IPTA, and the studies that were conducted are typically preliminary in nature. Notably, there is some evidence showing that the hypothalamic–pituitary–adrenal axis, various frontal and limbic brain regions, and behavioral indexes that represent brain functioning are associated with changes in IPT/IPT-A or predictive of IPT/IPT-A outcomes. We also consider consequences for treatment and future research. The hope is that a better understanding of how and for whom IPT/IPT-A works can optimize the success of the treatment in reducing an individual’s depressive symptoms.