Cadmium (Cd) is a common environmental pollutant that threatens humans’ and animals’ health. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs due to their wide therapeutic action; however, they have significant side effects. Since, under many circumstances, humans and animals may be co-exposed to Cd and NSAIDs, the current investigation was assigned to explore the intertwining relationship between Cd and NSAIDs. Four groups of male Wister rats were used: control group: rats received saline; Cd group: rats received cadmium (Cd, 2 mg/kg) orally; Px group: rats received a NSAID (piroxicam, Px, 7 mg/kg, i.p.); and Cd+Px group: rats received both Cd+Px. All treatments were given once a day for 28 consecutive days. Then, blood samples, stomach, liver, and kidney tissues were collected. The results indicated that Px provoked gastric ulcer indicated by high ulcer index, while Cd had no effect on the gastric mucosa. In addition, treatment with Cd or Px alone significantly induced liver and kidney injuries indicated by serum elevations of AST, ALT, ALP, ALB, total protein, creatinine, and urea along with histopathological alterations. Significant increases in malondialdehyde and reduction in GSH and CAT contents were reported along with up-regulated expression of Bax and Bcl-2 after Cd or Px exposure. However, when Cd and Px were given in a combination, Cd obviously potentiated the Px-inflicted cellular injury and death in the liver and kidney but not in the stomach when compared to their individual exposure. This study concluded that oxidative stress mechanisms were supposed to be the main modulator in promoting Cd and Px toxicities when given in combination.