Spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein Mire (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK happen to be developed as antineoplastic and anti-inflammatory therapeutics and also have also acquired interest as antiplatelet agents. Here, we investigate results of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and performance. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659 four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib) and 4 reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to bovine collagen, dense granule secretion, and alpha granule secretion as a result of the GPVI agonist mix-linked bovine collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the proportion of activated integrin αIIbβ3 around the platelet surface as a result of CRP-XL, as based on PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling occasions proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. Additionally, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet distributing on fibrinogen and differentially altered the business of PI3K around microtubules during platelets distributing on fibrinogen. Select TKIs also inhibited platelet aggregate formation on bovine collagen under physiological flow conditions. Together, our results claim that TKIs targeting Syk or BTK hinder central platelet functional responses but might differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.