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Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO₃) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO₃-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO₃'s immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO₃ or water (H₂O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO₃ led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFa + (M1-like) macrophages, M1-like/M2-like ratio, and SSC^high/SSC^low ratio of FSC^highCD11bc + cells, decreased in the spleen following NaHCO₃ administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO₃-induced immunomodulation. Artificial neural networks accurately classified NaHCO₃ and H₂O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO₃-induced immunomodulatory changes to the spleen, emphasizing NaHCO₃'s potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.