Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most common chronic liver disease, is characterized by endoplasmic reticulum (ER) stress, which impairs hepatic lipoprotein metabolism. Platelets, which can modulate cellular responses to ER stress, accumulate in the liver during MASLD and contribute to disease development by interacting with liver-resident (immune) cells. Since the role of platelets in modulating hepatic ER stress in vivo is completely unknown, this study aims to investigate their effects on hepatic ER stress and steatosis. Methods/Results: Using C57BL/6 mice, we demonstrate that hepatic ER stress leads to the accumulation and activation of platelets. Depletion of platelets decreased ER stress-induced liver steatosis, indicated by reduced liver triglyceride levels. Mechanistically, we found that platelet depletion ameliorated the initial ER stress response and increased the influx of neutrophils into the liver. Inhibiting the platelet-specific receptor glycoprotein 1bα (GPIbα) partly mimicked the effects of platelet depletion, leading to impaired hepatic platelet recruitment and reduced triglyceride accumulation. Conclusion: This study demonstrates a new role of platelets in hepatic ER stress and the concomitant effect on hepatic steatosis.