Spleen tyrosine kinase (Syk), a non‐receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll‐like receptor signalling to activate inflammatory responses following fungal infection but the role of this enzyme in zymosan (ZYM)‐induced non‐septic shock and its impacts on hypotension and inflammation in rats is not well understood. This study was conducted to determine the effects of Syk inhibition on ZYM‐induced alterations in the expression and/or activities of Syk, inhibitor ĸB (IĸB)‐α, and nuclear factor‐ĸB (NF‐ĸB) p65. We also examined the effect of Syk inhibition on inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‐2, and tumour necrosis factor (TNF)‐α, and activity of myeloperoxidase (MPO) that contributes to hypotension and inflammation. Administration of ZYM (500 mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate. These changes were associated with increased expression and/or activities of Syk, NF‐κB p65, iNOS and COX‐2 and decreased expression of IκB‐α with enhanced levels of nitrite, nitrotyrosine, 6‐keto‐PGF1α, and TNF‐α and activity of MPO in renal, cardiac and vascular tissues. ZYM administration also elevated serum and tissue nitrite levels. The selective Syk inhibitor BAY 61‐3606 (3 mg/kg, i.p) given 1 h after ZYM injection reversed all of these changes induced by ZYM. These results suggest that Syk/IĸB‐α/NF‐ĸB pathway activation contributes to hypotension and inflammation caused by the production of vasodilator and proinflammatory mediators in the zymosan‐induced non‐septic shock model. This article is protected by copyright. All rights reserved.