Few studies have investigated how Nogo-B affects sepsis-associated encephalopathy (SAE). Cannabinoid receptor 2 (CB2R) plays a critical role in regulating M1/M2 polarization in microglia. This study aimed to explore the association between CB2R and Nogo-B by assessing changes in microglial polarization markers.C57BL/6 mice with SAE induced by cecal ligation and puncture (CLP) surgery were intraperitoneally injected with HU308 for 3 consecutive days at the same time after that, and changes in cognitive function were assessed. After Lipopolysaccharides (LPS) and Interleukin-4 (IL-4) were used to induce BV2 microglial cell models respectively, HU308 and AM630 were applied to assess changes in inflammatory factors, microglial polarization markers, and the expression levels of CB2R and Nogo-B in microglial cells. We established a stable Nogo-B overexpression cell line. ELISA, Western blot, and flow cytometry were utilized to verify whether Nogo-B is a crucial protein in controlling BV2 cell polarization by HU308. There was an increase in Nogo-B protein expression during SAE. HU308 treatment alleviated the cognitive impairment of the CLP mice and markedly decreased the level of Nogo-B in the hippocampus tissues. The efficacy of CB2R activation to promote microglia polarization from M1 to M2 was diminished in BV2 cells overexpressing Nogo-B, although its anti-inflammatory effect was not entirely reversed. Inhibiting the Nogo-B expression, which in turn encourages the conversion of BV2 microglia to M2, attenuates inflammatory responses, and promotes neuronal repair, could be a key mechanism whereby activation of CB2R ameliorates septic encephalopathy.