Objective To investigate the effects of the polymer pharmaceutical excipient methoxy poly ethylene glycol poly-lactic acid (mPEG-PLA) in Sprague-Dawley (SD) rats and Beagle dogs and its toxicological reactions, to provide a reference for its safe clinical use. Methods SD rats and Beagle dogs (male:female ratios, 1 ∶ 1) were divided randomly into control group and low, medium, and high dose mPEG-PLA groups (70, 210, 700 mg/kg). Animals received intravenous mPEG-PLA once a day for 90 days, followed by a 28-day recovery period. Indicators including clinical observations, food intake, body weight, hematology, blood biochemistry, immune function, and pathological examination were recorded. Results Compared with the control group, (1)food intake was decreased (P<0.01) and body weight was increased (P<0.05 or P<0.01) after 90 days of continuous administration, with similar changes in the medium and high dose groups in both rats and dogs. In addition, MONO/ MONO%, RBC, MCH, MCHC, HCT, HGB, PLT, TP, ALB, GLB, and Fbg were all decreased (P<0.05 or P<0.01) and coagulation indexes (e.g., APTT) were increased (P<0.05 or P<0.01). Organ weights and the organ to-body/brain weight ratios of the liver and spleen were increased (P<0.05 or P<0.01), and histopathology indicated numerous foam-like macrophages in the hepatic sinuses, red spleen pulp, and lymph node medulla. DBIL and TBIL also increased in rats in the high dose group (P<0.05 or P<0.01), while the dogs experienced skin swelling or scabs, abdominal swelling, vomiting, decreased activity, high albuminuria, and ascites, and the renal glomerular cells showed vacuoles. (2)After 28 days of recovery, rats and dogs in the medium and high dose groups showed a few foam-like macrophages in the hepatic sinuses, red spleen pulp, and lymph node medulla, as well as decreased of food intake in dogs. The MCHC, PLT, and TP decreased in dogs in the high dose group (P<0.05), and the liver and spleen weights and organ coefficients in rats increased (P<0.05 or P<0.01), while the MONO% decreased in male rats in the medium dose group (P<0.05). Conclusions Administration of mPEG-PLA 210 and 700 mg/kg for 90 days caused blood mononuclear cells to enter and aggregate in the liver, spleen, lymph nodes, and other tissues in SD rats and Beagle dogs, leading to secondary tissue structural damage. Protein and fibrinogen synthesis and bilirubin metabolism in the liver decreased, leading to abnormal coagulation function, and decreased intravascular colloid osmotic pressure resulted in edema and bleeding. The result suggest that the liver, spleen, kidney, and lymph nodes are target organs for mPEG-PLA toxicity, with dose-dependent and reversible effects and species differences, but no significant sex differences. Clinical monitoring of related organ functions is needed to avoid secondary damage.