Background: Single intrahippocampal (IH) injection of amyloid beta (Aβ (1-42)) in rats causes mitochondrial dysfunction, oxidative stress, glial cell activation, and apoptosis hence results in cognitive dysfunction. Thus, the study was designed to evaluate the neuroprotective effect of coenzyme Q10 (CoQ10) and its modulation through minocycline (Mino) against Aβ (1-42) induced cognitive dysfunction and behavioral, biochemical, molecular and histological alterations. Methods: In the present study, Aβ (1-42) (1µg/µl saline) has been administered bilaterally to the hippocampal region of rat brain followed by chronic CoQ10 (20 and 40 mg/kg, i.p.), Mino (50 mg/kg, i.p.) and its combination administration for 21 days. Parameters like body weight and locomotor activity was evaluated weekly and Morris water maze (MWM) was performed in the last week and time spent in target quadrant (TSTQ) on day 21 followed by biochemical (lipid peroxidation, nitrite, catalase, reduced glutathione, catalase, superoxide dismutase, acetylcholinesterase), molecular (TNF-α level) and histopathological (H&E staining) parameters. Results: Single bilateral IH Aβ (1-42) administration results in reduction of body weight, marked motor impairment, impaired cognitive performance (MWM and TSTQ), increased oxidative stress, increased inflammatory cytokines and histopathological alterations. However, chronic treatment with CoQ10 (20 and 40 mg/kg) and Mino (50 mg/kg) treatment significantly attenuated behavioral parameters, acetylcholinesterase level and oxidative damage and TNF-α level and histopathological alterations. Further, combination of CoQ10 (40 mg/kg) with Mino (50 mg/kg) significantly potentiated their protective effect as compared to their effect alone. Conclusion: The present study highlights the involvement of possible microglia modulatory mechanism of CoQ10, minocycline and their combination against IH Aβ (1-42) induced oxidative damage and neuroinflammation.