In this study, we tested a novel synthetic pyrazole‐containing compound, 5‐amino‐1‐phenyl‐1H‐pyrazole‐4‐carbonitrile (APPC), as an antioxidant in both in vitro and in vivo models of oxidative stress. In addition, the utility of covalently combining APPC with another well‐established antioxidant, lipoic acid (LA), was also tested in both models. The in vitro results demonstrated that pretreatment with APPC in a mixed neuronal‐glial culture exposed to oxygen‐glucose deprivation (OGD) followed by reoxygenation‐refeeding, resulted in significant neuroprotection at concentrations between 2.5 to 25 μmol/L. In contrast, LA was not neuroprotective following OGD alone or following reoxygenation‐refeeding. However, the synthetic covalent combination of APPC with LA, named “UPEI‐800”, resulted in significant neuroprotection at concentrations between 0.027 and 2.7 μmol/L (100‐fold more potent than APPC alone), an effect shown to be correlated with increased cellular antioxidant capacity. Further, in an in vivo model of ischaemia‐reperfusion injury following transient occlusion of the middle cerebral artery (tMCAO), both APPC (0.1 and 1.0 mg/kg) and UPEI‐800 (1×10−3 mg/kg) provided significant neuroprotection. Consistent with the in vitro findings, the in vivo results following tMCAO also demonstrated a 100‐fold increase in the potency of the covalently linked compound UPEI‐800 compared to APPC alone.