Microcystin- (MC-) LR is the most frequent cyanotoxin produced by Microcystis aeruginosa cyanobacteria in the contaminated freshwater environment. MC represents a health hazard to humans and animals. Therefore, the present study was designed to evaluate the potential ameliorative effect of thymoquinone (TQ) and/or piperine (PP) against MC toxicity in mice. Fifty-six mice were randomly divided into seven experimental groups. Group I is the normal control that received distilled water for 21 days; Group II (TQ) was treated with TQ (10 mg/kg, i.p) for 21 days; Group III (PP) was treated with PP (25 mg/kg, i.p) for 21 days; Group IV (MC) was treated with MC (10 μg/kg, i.p) for 14 days and served as the toxic control; and Groups V, VI, and VII received TQ and/or PP 7 days prior to MC and continued for 14 days with MC. The results revealed that MC elicited hepatotoxicity and neurotoxicity which was evident due to the significant elevation of serum AST, ALT, γGT, ALP, LDH, IL-1β, IL-6, and TNF-α levels. Furthermore, MC markedly increased MDA and NO contents along with reduction of GSH, SOD, CAT, and GSH-Px in liver and brain tissues. The electron transport chain may be a possible target for MC. TQ and/or PP ameliorated the MC-mediated oxidative damage in the liver and brain which might be attributed to their antioxidant properties. However, the concurrent treatment of TQ and PP showed the best regimen as a result of the PP-enhanced bioavailability of TQ.