In this study, we evaluated the effectiveness of UV-LED-irradiated TiO2 in removing 24 commonly detected PPCPs in two water matrices (municipal wastewater effluent and Suwannee River NOM–synthetic water) and compared their performance with that of ultrapure water. Relatively fast removal kinetics were observed for 29% and 12% of the PPCPs in ultrapure water and synthetic surface water, respectively (kapp of 1–2 min−1). However, they all remained recalcitrant to photocatalysis when using wastewater effluent as the background matrix (kapp < 0.1 min−1). We also observed that the pH-corrected octanol/water partition coefficient (log Dow) correlated well with PPCP degradation rate constants in ultrapure water, whereas molecular weight was strongly associated with the rate constants in both synthetic surface water and wastewater. The electrical energy per order (EEO) values calculated at the end of the experiments suggest that UV-LED/P25 can be an energy-efficient method for water treatment applications (2.96, 4.77, and 16.36 kW h m−3 in ultrapure water, synthetic surface water, and wastewater effluents, respectively). Although TiO2 photocatalysis is a promising approach in removing PPCPs, our results indicate that additional challenges need to be overcome for PPCPs in more complex water matrices, including an assessment of photocatalytic removal under different background water matrices.