Tramadol is a popular drug of abuse among adolescent and young adults in many developing African countries due to the opioid agonist properties. We investigated the health implications of the sub-chronic concurrent abuse of tramadol, caffeinated drink and alcohol in adult male Wistar rats. Tramadol was administered at 40 and 20 mg/kg BW respectively, caffeinated drink at 10 ml/kg BW and alcohol at 2 ml/kg BW. The rats were handled such that: group A received distilled water; groups B and C received tramadol and distilled water; groups D and E received tramadol and caffeinated drink; groups F and Greceived tramadol and alcohol; and groups H and I received caffeinated drink and alcohol respectively. The concentrations of nitric oxide (NO), reduced glutathione (GSH),malondialdehyde (MDA),protein carbonyl (PC),protein thiol (PT), interleukin 1β (IL-1β), vascular cell adhesion molecule (VCAM-1), monocyte chemotactic protein-1 (MCP-1), oxidized low density lipoprotein cholesterol (ox-LDLC), and activities of paraoxonase (PON-1) and acetylcholine esterase (ACE) were determined. Histo-pathological analysis was performed on the liver, kidney, brain and small intestine. The concentrations of blood nitric oxide, GSH and MDA increased (p0.05). Inconsistent alterations were obtained in blood PON-1 activities across the groups. Decreases were recorded in the GSH and TPT in the liver and brain with increases in PC and MDA (p<0.05). Inconsistent increases were obtained in the concentrations ox-LDLC, VCAM-1, IL-1β and MCP-1, and ACE activities. Consistent alterations were observed in the photomicrographs of the brain, kidney, intestine and liver of rats co-administered 40 mg/kg BW of tramadol withcaffeinated drink or alcohol. The overall findings indicated that the use of tramadol singly at 40 mg/kg BW or co-administered at both doses with caffeinated drink and alcohol precipitated various dysfunctions to health that could reduce the quality of life.