Robustness of a demonstration potable reuse facility was evaluated through a series of system-wide chemical challenge tests spiking neutral low-molecular weight compounds (acetone, formaldehyde, N-nitrosodimethylamine (NDMA), and 1,4-dioxane) which are known to be challenging for removal through advanced treatment. Two advanced treatment train arrangements were compared: O3/BAC-MF/UF-RO-AOP and RO-AOP. Ozone and biological activated carbon (O3/BAC) offered significant attenuation of the smallest and most biologically degradable compounds tested: acetone and formaldehyde. These two compounds had limited reduction across the reverse osmosis (RO) membrane barrier and the different advanced oxidation process (AOP) setups used. 1,4-Dioxane was partially reduced across the oxidation barriers: 62% across ozonation and up to 95% across AOP depending on oxidant used and oxidant dose. Both a hydrogen peroxide (H2O2) based AOP (UV/H2O2) and a sodium hypochlorite (as HOCl) based AOP (UV/HOCl) demonstrated sufficient oxidation, providing no less than 0.5-log (68%) 1,4-dioxane attenuation required by regulators in the USA. NDMA was reduced across both UV/H2O2 and UV/HOCl from 157 to 267 ng/L to below the 10 ng/L established notification level for drinking water in California. Overall, addition of O3/BAC enhanced cumulative removal of all the spiked trace organic chemicals, providing greater protection against the spiked contaminants than RO-AOP alone. In addition, online total organic carbon (TOC) monitoring successfully captured the presence of the spiked chemicals.