Accumulating evidence suggests that Propionibacterium acnes (P. acnes) is a novel pathogenic factor promoting intervertebral disc degeneration (IVDD). However, the underlying mechanisms by which P. acnes induces IVDD have been unclear. In this study, we quantified the severity of IVDD, as well as the expressions of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase (COX-2)/prostaglandin (PGE2) in human intervertebral discs (IVDs) infected with P. acnes. Compared with P. acnes-negative IVDs, P. acnes-positive IVDs showed increased iNOS/NO and COX-2/PGE2 activity concomitant with more severe IVDD. In order to detect the potential correlation between iNOS/NO expression, COX-2/PGE2 expression, and IVDD, we developed a P. acnes-induced IVDD rat model and found that the upregulation of iNOS/NO and COX-2/PGE2 was essential to the occurrence of P. acnes-induced IVDD. This finding was supported by the fact that the inhibition of iNOS/NO and COX-2/PGE2 activity ameliorated IVDD significantly, as evidenced by restored aggrecan and collagen II expression both in vivo and in vitro. Mechanistically, we found that P. acnes induced iNOS/NO and COX-2/PGE2 expressions via a reactive oxygen species- (ROS-) dependent NF-κB cascade. Furthermore, NADPH oxidase participated in P. acnes-induced ROS, iNOS/NO, and COX-2/PGE2 expressions. Overall, these findings further validated the involvement of P. acnes in the pathology of IVDD and provided evidence that P. acnes-induced iNOS/NO and COX-2/PGE2 activation via the ROS-dependent NF-κB pathway is likely responsible for the pathology of IVDD.