Abstract: Background and Objective: Doxorubicin (an anti-cancer drug), acetaminophen (a non-steroidal anti-inflammatory drug) and first-line anti-tubercular drugs (rifampicin, isoniazid and pyrazinamide) have been used to induce organ toxicity in animal experiments. Despite many respective reports on their organ toxicities, there is a lack of literature on studies aimed at comparing the pattern of injuries exerted by these drugs on the microanatomical structures of the liver and kidney tissues in vivo. The present study, for the first time, demonstrated and compared the effects of doxorubicin (DOX), acetaminophen (APAP) and first line anti-tubercular drugs (ATB) on body weights, relative organ weights and light microscopical features of the liver and kidneys of albino rats. Materials and Methods: Male albino rats in respective groups were treated with intra-peritoneal doses of DOX (20 mg kg–1), oral doses of APAP (500 mg kg–1) and ATB drugs (200 mg kg–1 rifampicin+150 mg kg–1 isoniazid+500 mg kg–1 pyrazinamide), once daily for 7 days. The effects of the treatments on relative organ weights and histopathology of the liver and kidney were determined. Results: The body weight loss was observed in all treatment groups when compared to the control (p<0.05). The liver index decreased in DOX and APAP groups while the kidney index increased in DOX and ATB groups when compared to the control (p<0.05). Histopathological studies revealed characteristically distinctive patterns of injuries in the liver and kidney of rats in the three different groups with the DOX group showing the most profound deleterious changes. Conclusion: Findings obtained from this study provide the light microscopical in vivo evidence of hepatotoxicity and nephrotoxicity by the DOX, APAP and ATB after a short-term administration, with DOX exerting the most profound microanatomical alterations in the liver and kidney tissues.