Background and Aim The many pharmacological potentials of Stachytarpheta cayennensis (L.C. Rich) Vahl, especially in managing central nervous system disorders, hypertension, diabetes and infections, have made it a subject of abuse, necessitating the need to ascertain its safety. This study therefore investigated the toxic effects of the leaf extract of S. cayennensis in rats following acute and 28-day repeated doses in male and female rats. Experimental procedure Acute and repeated dose studies were conducted in male and female groups of rats (135–150 g), using OECD 423 and 407 Tests guidelines respectively. Functional observational battery, and body weights were monitored. Blood samples were analysed for haematological and plasma biochemical indices. Organs (brain, kidneys and liver) specimen were collected and weighed. Kidney and liver specimen were subjected to histopathological analysis. Results and conclusion The LD 50 of the extract was greater than 5000 mg/kg, p.o. (24 h) suggesting that the extract may be non-toxic. However, following single and repeated doses, the results revealed varying degree of significant (p < 0.05) changes in biochemical and heamatological indices, as well as in relative body weight and organ-body and organ-brain weight ratios. Also, histological assessment revealed evidence of liver and kidney toxicities and recovery was incomplete, as signs of toxicities were still evident after 21 days of recovery. Therefore, the extract is potentially harmful to vital organs with evidence of sex differential adverse effects and non-reversible forms of toxicity, especially with repeated usage, necessitating the need to avoid indiscriminate use.