Remibrutinib inhibited B-cell–dependent HuMOG EAE at daily oral doses of 3 and 30 mg/kg and strongly reduced neurological symptoms. The ex vivo MOG-specific T-cell recall response was inhibited, but the polyclonal T-cell response was not, indicating selective B-cell inhibition. Remibrutinib did not decrease total immunoglobulin G antibody levels. Remibrutinib demonstrated strong BTK occupancy in the peripheral immune organs and brain at the efficacious dose of 30 mg/kg. Remibrutinib also inhibited RatMOG EAE, indicating that myeloid cell and microglia inhibition contributes to its efficacy in MS; this is supported by anti-inflammatory effects detected via single-cell RNA sequencing of the mouse brain and spinal cord. Remibrutinib also significantly reduced neurofilament light chain levels in serum.