Mitochondria are the target sites for multiple disease manifestations, for which it is appealing to researchers' attention for advanced pharmacological interventions. Mitochondrial inhibitors from natural sources are of therapeutic interest due to their promising benefits on physiological complications. Mitochondrial complexes I, II, III, IV, and V are the most common sites for the induction of inhibition by drug candidates, henceforth alleviating the manifestations, prevalence, as well as severity of diseases. Though there are few therapeutic options currently available on the market. However, it is crucial to develop new candidates from natural resources, as mitochondria-targeting abnormalities are rising to a greater extent. Marine and terrestrial sources possess plenty of bioactive compounds that are appeared to be effective in this regard. Ample research investigations have been performed to appraise the potentiality of these compounds in terms of mitochondrial disorders. So, this review outlines the role of terrestrial and marine-derived compounds in mitochondrial inhibition as well as their clinical status too. Additionally, mitochondrial regulation and, therefore, the significance of mitochondrial inhibition by terrestrial and marine-derived compounds in drug discovery are also discussed.