Objective: Diabetes mellitus (DM) is a common metabolic disorder. Type 1 diabetes (T1D) can cause hepatopathies as the liver is the primary organ of glucose metabolism. This study sought to investigate the possible protective effects of trimetazidine (TMZ) on T1D liver disease and the mechanism underlying these effects through alleviation of endoplasmic reticulum stress-mediated NLRP3 inflammasome activation. Methods: Twenty-four Sprague–Dawley rats were equally divided into four groups: control, TMZ, T1D, and T1D + TMZ groups. After killing, blood samples were collected to assess glucose, insulin, ALT, AST, and IL-1β. Livers were harvested and divided into left and right lobes. The left lobe was further divided into part preserved for IRE1, CHOP, and NLRP3 mRNA expression and the other part homogenized for colorimetric measurement of malondialdehyde (MDA). The right lobe was preserved for histopathological assessment and immunohistochemical assessments of NLRP3 and caspase-1. Results: Trimetazidine ameliorated T1D-induced liver damage. TMZ significantly reduced MDA levels and the ER stress markers inositol requiring enzyme (IRE1) and C/EBP homologous protein (CHOP), leading to suppression of NLRP3 inflammasome activation, IL-1β, and caspase-1 dependent pyroptosis. Additionally, TMZ improved hepatic histological architecture. Conclusions: These results demonstrate a hepatoprotective role for TMZ in T1D-induced liver injury, potentially mediated through suppression of ER stress, inflammation, and caspase-1-dependent pyroptosis.