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Stimulation of naïve T cells during primary infection or vaccination drives the differentiation and expansion of effector and memory T cells that mediate immediate and long-term protection. Despite self-reliant rescue from infection, BCG vaccination, and treatment, long-term memory is rarely established against Mycobacterium tuberculosis (M.tb) resulting in recurrent tuberculosis (TB). Here, we show that berberine (BBR) enhances innate defense mechanisms against M.tb and stimulates the differentiation of Th1/Th17 specific effector memory (TEM), central memory (TCM), and tissue-resident memory (TRM) responses leading to enhanced host protection against drug-sensitive and drug-resistant TB. Through whole proteome analysis of human PBMCs derived from PPD+ healthy individuals, we identify BBR modulated NOTCH3/PTEN/AKT/FOXO1 pathway as the central mechanism of elevated TEM and TRM responses in the human CD4+ T cells. Moreover, BBR-induced glycolysis resulted in enhanced effector functions leading to superior Th1/Th17 responses in human and murine T cells. This regulation of T cell memory by BBR remarkably enhanced the BCG-induced anti-tubercular immunity and lowered the rate of TB recurrence due to relapse and re-infection. These results thus suggest tuning immunological memory as a feasible approach to augment host resistance against TB and unveil BBR as a potential adjunct immunotherapeutic and immunoprophylactic against TB. Author summary In response to primary infections or vaccination, the host immune system elicits robust effector and memory responses to facilitate immediate pathogen clearance and to establish long-term protection. In this study, we have ascertained the prospects of potent immunomodulator berberine (BBR) in instigating host protective immunological memory responses during tuberculosis (TB). BBR-induced glycolytic flux stimulates pro-inflammatory immune responses against Mycobacterium tuberculosis (M.tb). BBR further prompted NOTCH-mediated AKT inhibition and activation of FOXO1, STAT3, STAT4, BLIMP-1, and NFκB signaling thereby enriching M.tb-specific resident memory T cell population in the distinct murine TB disease models and human CD4+ T cells. These results project BBR as an adjunct immunotherapeutic and immunoprophylactic against TB.