Piroxicam is a non-steroidal anti-inflammatory drug that is effective in treating pain and inflammation in the body. The safety profile of Piroxicam is influenced by episodic and sporadic abuse, in addition to adverse pharmacological reactions. The aim of the study is to investigate the effect of Piroxicam on the uterus and ovaries of female Sprague-Dawley rats. Twenty female rats were used and divided into four groups each (A-D: n-5) and received 0,10,20 and 40 mg/kg of Piroxicam orally for 28 days, then euthanized and the following were assessed: histological damage to the ovary and uterus, possible changes in some hormonal level, and oxidative stress levels. Piroxicam significantly suppressed the levels of SOD and CAT, and increased the level of MDA in rats. Piroxicam showed an irregular pattern in the level of Progesterone, LH, and Estrogen. Uterine sections showed mild to severe infiltration of the endometrial stroma by inflammatory cells, while ovarian sections showed moderate to mild vascular congestion in the ovaries. Results showed that chronic use of Piroxicam produces a deleterious effect on the histoarchitecture of the ovaries and uterus, as well as changes in hormone levels and oxidative stress.