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Diclofenac sodium salt (DSS) is a widely used nonsteroidal anti-inflammatory drug. The present study was performed under good laboratory practice (GLP) regulations to investigate the toxicity of DSS after 4 weeks of repeated intramuscular administration at doses of 0, 2, 10, or 20 mg/kg/day in 32 minipigs and to evaluate the DSS effect following a 2-week recovery period. Dose-related clinical signs and alterations of hematological or clinical chemistry parameters, organ weight, and macroscopic as well as histopathological findings in hepatic, renal, gastrointestinal, skin and injection sites were observed in both sexes’ animals of the 10 or 20 mg/kg/day group. With the exception of the skin-related findings, most symptoms showed a tendency to resolve after the 2-week recovery period. The systemic exposure (AUClast) of DSS in plasma showed similar pattern to the increase rate of the dose and similar values between males and females except for the female 20 mg/kg dose group (56 %) on Day1. The systemic exposure showed a decreasing trend in the 10 or 20 mg/kg group after 4-week of repeated administration compared to Day1. The no-observed-adverse-effect level of DSS in this study was considered to be 2 mg/kg/day in both male and female minipigs.