Abstract: Vinpocetine (Vinpo) is a neuroprotective vasodilator drug. It is an effective therapeutic agent for a variety of cerebrovascular and cognitive disorders. However, its potential protective efficacy on intestinal ischemia/reperfusion (I/R) injury remains elusive. The present study aimed to investigate the effect of Vinpo on intestinal I/R injury and to explore its modulatory effect on sirtuin (SIRT1)/ Suppressor of cytokine signaling (SOCS3)/Signal Transducer and Activator of Transcription (STAT3) signaling. Twenty-four male Wistar albino rats were randomly allocated into four groups. G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/2-h I/R, GIII (Vinpo + I/R): rats were pre-treated with Vinpo (20 mg/kg/day, P.O. daily) for 2 weeks before intestinal I/R; GIV (EX527 + Vinpo + I/R): rats received both Vinpo (20 mg/kg/day, P. O.) and EX527 (5 mg/kg, once every 2 days, i.p) for 2 weeks before intestinal I/R. The current results showed that Vinpo improved the intestinal histopathological picture, enhanced M1 to M2 macrophage polarization and alleviated the I/R-induced increase in interleukins (IL-6, IL-1β), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (i-NOS), and nitric oxide (NO). Additionally, Vinpo pretreatment upregulated SIRT1 mRNA expression/protein level and SOCS3 mRNA expression while downregulating P-STAT3 immunoreactivity. The effects of Vinpo were attenuated by the SIRT1 inhibitor EX527. We concluded that Vinpo ameliorated the intestinal I/R injury and enhanced M2 anti-inflammatory macrophage polarization through modulation of SIRT1/SOCS3/STAT3/i-NOS cascade.