Our previous study has reported that the pentose phosphate pathway product nicotinamide adenine dinucleotide phosphate (NADPH) protected neurons against ischemia/reperfusion-induced brain injury. NADPH can either act as a co-enzyme to produce GSH or a substrate of NADPH oxidase (NOX) to generate ROS. This study was designed to elucidate the effects of co-treatment with NADPH and NOX inhibitor apocynin on ischemia/reperfusion-induced brain inflammation and neuronal injury. The results showed that both NADPH and apocynin markedly attenuated ischemia/reperfusion-induced increases in the levels of NOX2, NOX4 and ROS. NADPH and apocynin significantly inhibited the phosphorylation and degradation of IκBα, NF-κBp65 nuclear localization, and the expression of NF-κB target gene cyclooxygenase (COX2) and inducible nitric oxide synthase (iNOS). Furthermore, both NADPH and apocynin suppressed the expression of inflammasome proteins including NLRP3 ASC, caspase-1, interleukin (IL)-1β and IL-18 in the ischemic cortex as revealed by Western blot analysis and immunofluorescence. Moreover, all these effects were greatly amplified by combination of NADPH and apocynin. Both NADPH and apocynin significantly reduced infarct volume, improved post-stroke survival, and recovery of neurological functions in mouse model of stroke. Consistently, the combination of NADPH and apocynin produced greater beneficial effects in against ischemic brain damage. These studies suggest that, beyond anti-oxidative effects, NADPH may also have anti-inflammatory effects and combination of NADPH and NOX inhibitors could produce a greater neuroprotective effect in ischemic stroke.