The mechanisms regarding the retinal protective and anti‐inflammatory effects of capsaicin (CAP) remain unclear. Somatostatin is contained in CAP‐sensitive sensory neurons, including nerve terminals, from which it can be released by capsaicin. The present study provides a novel neurohumoral regulatory mechanism for CAP‐induced‐endogenous somatostatin in a retinal ischemic‐reperfusion (I/R) mouse model. CAP (0.5 mg kg−1) was injected subcutaneously 5 min after I/R. A selective somatostatin‐depleting agent, cysteamine, was applied subcutaneously 4 hours before the experiment to examine the effects of endogenous somatostatin. Ischemia and oxidative stress‐induced inflammatory factors (CXCL10, CXCR3 and NF‐κB p65) were also examined in the present study. The morphometric evaluation showed that the retinal thickness was increased 24 hours after I/R injury and attenuated 7 days after I/R injury. The number of ganglion cells was reduced 7 days after I/R injury. The application of CAP significantly prevented retinal I/R damage. Cysteamine pretreatment reversed the effects of CAP. Inhibition of CXCL10/CXCR3 and NF‐κB (especially in astrocytes and microglia/macrophage) was involved in capsaicin‐induced retinal protection through endogenous somatostatin. CAP has anti‐inflammatory and neuroprotective effects in ischemia‐induced retinal injuries through endogenous somatostatin. Novel therapeutic remedies for inflammation or neuronal injuries were developed based on the systemic humoral effects related to CAP. This article is protected by copyright. All rights reserved.