Botanical extracts are recognized in traditional medicine for their therapeutic potential and safety standards. Botanical extracts are viable and sustainable alternatives to synthetic drugs, being essential in drug discovery for various diseases. Senna septemtrionalis (Viv.) H.S. Irwin & Barneby is a medical plant traditionally used to treat inflammation. However, its antioxidant and anti-inflammatory properties and the molecular pathways activated in microglial cells require further investigation. Therefore, this study examines the antioxidant and anti-inflammatory properties of Senna septemtrionalis (Viv.) H.S. Irwin & Barneby methanol extracts (SMEs) in lipopolysaccharide (LPS)-stimulated mouse microglial cells. SMEs significantly inhibit LPS-induced nitric oxide (NO) and proinflammatory cytokine production, which are mediated through the dephosphorylation of mitogen-activated protein kinases and inhibition of nuclear factor kappa B (NF-κB) translocation into the nucleus. Additionally, SME treatment upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1, reducing oxidative stress, indicated by a decrease in reactive oxygen species and restoration of the total glutathione content in LPS-stimulated BV2 cells. The inhibitory effects of SMEs on inflammatory mediator production and NF-κB nuclear translocation were significantly reversed by Sn-protoporphyrin, a specific HO-1 inhibitor. These findings demonstrate that SME protects microglial cells by activating the Nrf2/HO-1 pathway and inhibiting NF-κB translocation.