J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evobrutinib was determined using kinase assays and purified, full-length recombinant BTK at various concentrations. The effect of evobrutinib on BTK phosphorylation after BCR activation was determined in Ramos B cells. Evobrutinib’s ability to block BCR signalling was determined using B cells in whole blood or purified peripheral blood mononuclear cells. CD19+ B cells of healthy volunteers were used to conduct B cell proliferation, cytokine release, and plasmablast differentiation assays. The collagen-induced arthritis murine models was used to examine inflammation, cartilage damage, and bone resorption. Lupus was modelled using the NZB/W F1 murine model. Evobrutinib showed greater selectivity compared with ibrutinib as seen in a kinome tree format. Out of a panel of 267 kinases, evobrutinib inhibited BTK, BMX, and TEC by 90, 93, and 82%, respectively. Evobrutinib was associated with the inhibition of a range of B cell functions induced by BCR stimulation, including proliferation, cytokine production, and Ig production. Incidence and severity of clinical disease signs were reduced in a dose-dependent fashion with a dose of 3 mg/kg almost completely preventing the development of arthritis symptoms and structural damage. For both RA and SLE disease models, near-maximal inhibition of disease activity is predicted when an average occupancy of >80% at pharmacodynamic steady state is reached. These results suggest evobrutinib is a promising molecule for B cell-driven autoimmune disorders.