Platelet C-type lectin-like receptor 2 (CLEC-2) is a hem-immunoreceptor tyrosine-based activation motif-containing receptor that has a critical role in venous thrombosis but minimal involvement in hemostasis. CLEC-2 can be blocked by Btk inhibitors. Treatment with ibrutinib is associated with increased bleeding due to off-target inhibition of Src family kinases (SFKs). Patients with X-linked agammaglobulinemia (XLA) who lack Btk, however, do not bleed, suggesting selective Btk inhibition as a viable antithrombotic strategy. We assessed the effects of selective Btk inhibitors PRN1008 (rilzabrutinib) and PRN473 on platelet signaling and function mediated by CLEC-2 and glycoprotein-VI. We used healthy donors and XLA platelets to determine off-target inhibitor effects. Inferior vena cava (IVC) stenosis and Salmonella infection mouse models were used to assess antithrombotic effects of PRN473 in vivo. PRN1008 and PRN473 potently inhibited CLEC-2-mediated platelet activation to rhodocytin. No off-target inhibition of SFKs was seen. PRN1008 treatment of Btk-deficient platelets resulted in minor additional inhibition of aggregation and tyrosine phosphorylation, likely reflecting inhibition of Tec. No effect on G protein-coupled receptor-mediated platelet function was observed. PRN473 significantly reduced the number of thrombi in podoplanin-positive vessels after Salmonella infection and the presence of IVC thrombosis after vein stenosis. The potent inhibition of human platelet CLEC-2 and reduced thrombosis in in vivo models, together with the lack of off-target SFK inhibition and absence of bleeding reported in rilzabrutinib-treated patients with immune thrombocytopenia, suggest Btk inhibition as a promising antithrombotic strategy.