The large volume of oil sands process-affected water (OSPW) produced by the oil sands industry in Northern Alberta, Canada, is an environmental concern. The toxicity of OSPW has been attributed to a complex mixture of naturally occurring acids, including naphthenic acids (NAs). Highly cyclic or branched NAs are highly biopersistent in tailings ponds, thus understanding structure–reactivity relationship for NAs is very important for OSPW reclamation. In this study, we hypothesized that large, branched and cyclic NAs may be better oxidized in the UV/H2O2 process than small, linear and acyclic NAs. Relative rate measurements using binary mixtures of model NA compounds confirmed that reactivity favored compounds with more carbons, and also favored NAs with one saturated ring, relative to the corresponding linear NA. However, for model compound with three rings, no increased reactivity was observed relative to monocyclic NA. UV/H2O2 treatment of OSPW confirmed our findings with model compounds, indicating that the compounds with more carbons are favored for degradation. However, increasing the number of rings (or double bond equivalents) in OSPW NAs did not show any clear structure–reactivity. Microbial degradation studies of the UV/H2O2 treated OSPW should be conducted to examine the overall benefit of this treatment for the real applications.