Introduction: Minocycline has been demonstrated to have potent effects on neurologic structures and functions in several animal models. However, its neuroprotective properties following a single injection of lipopolysaccharide (LPS) in an adult rat model have not been clearly elucidated. This study investigated minocycline’s neuroprotective effects in the LPS-induced neuroinflammation rat model. Methods: Fifty adult male Sprague Dawley rats were split into five groups at random: (i) control, (ii) distilled water-treated LPS, (iii) 25 mg/kg minocycline-treated LPS, (iv) 50 mg/kg minocycline-treated LPS, and (v) 10 mg/kg memantine-treated LPS. On day 5, LPS (5 mg/kg) was given intraperitoneally once, whereas minocycline and memantine were given once daily for 14 days. Results: LPS was found to significantly induce β-amyloid peptide deposition and neuronal damage, and impair recognition memory, while administration of minocycline dose-dependently reversed these effects. These data suggest that LPS-induced recognition memory impairment by inducing β-amyloid peptide deposition and neuronal damage in the cortical and hippocampal areas. Furthermore, we compared minocycline with memantine administration, and these data suggested better effects in minocycline (50 mg/kg) and comparable effects between minocycline (25 mg/kg) and memantine (10 mg/kg) treatments in reducing β-amyloid peptide deposition, neuronal damage and recognition memory impairment induced by LPS. Conclusion: Minocycline may be a strong contender as an effective preventive-therapeutic drug for neuroinflammatory diseases such as Alzheimer’s disease (AD) based on these findings.