Sigma 1 receptor (S1R), a ligand-regulated chaperone mainly located in the mitochondrion-associated endoplasmic reticulum membrane (MAM), has emerged as a potential target for chronic pain and depression. Over the past decades, numerous studies on chronic pain and depression have been conducted, aiming to find more effective therapies. However, the complex pathophysiological processes of these conditions limit the effectiveness of many clinical treatments. Hence, this review provides an overview of the elucidation of the modulatory effects and underlying mechanisms of S1R in chronic pain and depression, as well as their comorbidity. Preclinical studies have demonstrated that S1R antagonists or S1R knockout (KO) mice may provide potential benefits in reversing hypersensitivity in various animal pain models. Meanwhile, S1R agonists have the potential to alleviate depression-like behaviors in rodents. Notably, controversy remains regarding the effect of S1R on comorbid conditions in preclinical studies. Since S1R antagonists may result in depression and agonists might trigger hyperalgesia, receptor diversity should be considered in drug development to avoid side effects. The mechanisms underlying the analgesic and antidepressant-like effects of S1R may involve interactions with TRPA1 and TRPV1 ion channels; NMDA and MOR receptors; modulation of glutamatergic/GABAergic neurotransmission; and regulation of the BDNF/TrkB signaling pathway. Consequently, S1R serves as a possible target for the development of painkillers and antidepressants.Copyright © 2025. Published by Elsevier B.V.