Oil sands process water (OSPW) is an industrial process effluent that contains organic compounds such as naphthenic acids (NAs) and polyaromatic hydrocarbons (PAHs), as well as large quantities of inorganic compounds in its mixture. OSPW requires effective treatment for successful reclamation and water reuse. This study investigated the impact of solar-activated zinc oxide (ZnO) photocatalysis on the degradation and removal of NAs and PAHs in OSPW, as well as the elimination of its acute toxicity. With catalyst particles suspended in the effluent (at 1 g/L) under simulated solar radiation of steady irradiance of ~278 W/m2, more than 99% removal of NAs was achieved after 4 h of treatment, while nearly all PAHs were simultaneously oxidized within the same reaction time. The photocatalytic treatment appeared to selectively convert classical NAs faster than oxidized NAs. Additionally, NAs with higher double-bond equivalents (DBEs) and higher carbon numbers seemed more susceptible to photocatalytic destruction than others. An overall pseudo first-order rate constant of 1.14 × 10−2 min−1, and a fluence-based rate constant of 6.81 × 10−1 m2/MJ were recorded in apparently hydroxyl radicals (OH) and superoxide (O2−) radicals mediated NAs degradation mechanisms. Assessment of the toxicity levels in raw and treated OSPW samples by using Microtox® bioassay indicated that the photocatalytic treatment resulted in ~50% reduction in acute toxicity. Furthermore, we showed that by monitoring the expression levels of key proinflammatory genes using qPCR that treated OSPW significantly reduced the ability of raw OSPW to activate the inflammatory response of immune cells. This indicates that at acute sub-lethal exposure doses, photocatalytic treatment also reduces immunotoxicity. Overall, our results suggest that the ZnO-based photocatalytic degradation of these NAs and PAHs in OSPW could be a significant treatment process aimed at detoxifying OSPW.