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Multiple sclerosis (MS) remains a leading cause of neurological disability, primarily due to the limited efficacy of current disease-modifying therapies in arresting progressive neurodegeneration. While peripheral lymphocyte depletion effectively manages relapsing activity, it fails to address the compartmentalized, smoldering inflammation driven by interactions between adaptive and innate immune systems within the central nervous system (CNS). The CD40–CD40L costimulatory pathway has emerged as a central regulator of these immune interactions, positioning it as a unique therapeutic target capable of addressing the full spectrum of MS pathology. This review examines the multimodal effects of CD40L blockade across peripheral and CNS-resident cell populations. Preclinical and genetic models demonstrate that inhibiting this axis suppresses pathogenic T-cell and B-cell responses while modulating innate immune activation, including macrophages, microglia, and astrocytes, and disrupting pro-inflammatory glial crosstalk. Early clinical data from second-generation, non-thromboembolic CD40L inhibitors, such as frexalimab, demonstrate reductions in markers of neuroaxonal injury and inflammatory disease activity. By simultaneously modulating systemic lymphocyte responses and CNS-resident innate immune processes, CD40L blockade represents a promising strategy to address both relapsing disease activity and progressive disability accumulation, thereby overcoming key therapeutic barriers in multiple sclerosis.