The performance of ozonation in wastewater depends on water quality and the ability to form hydroxyl radicals ( OH) to meet disinfection or contaminant transformation objectives. Since there are no on-line methods to assess ozone and OH exposure in wastewater, many agencies are now embracing indicator frameworks and surrogate monitoring for regulatory compliance. Two of the most promising surrogate parameters for ozone-based treatment of secondary and tertiary wastewater effluents are differential UV254 absorbance (ΔUV254) and total fluorescence (ΔTF). In the current study, empirical correlations for ΔUV254 and ΔTF were developed for the oxidation of 18 trace organic contaminants (TOrCs), including 1,4-dioxane, atenolol, atrazine, bisphenol A, carbamazepine, diclofenac, gemfibrozil, ibuprofen, meprobamate, naproxen, N,N-diethyl-meta-toluamide (DEET), para-chlorobenzoic acid (pCBA), phenytoin, primidone, sulfamethoxazole, triclosan, trimethoprim, and tris-(2-chloroethyl)-phosphate (TCEP) (R2 = 0.50–0.83) and the inactivation of three microbial surrogates, including Escherichia coli, MS2, and Bacillus subtilis spores (R2 = 0.46–0.78). Nine wastewaters were tested in laboratory systems, and eight wastewaters were evaluated at pilot- and full-scale. A predictive model for OH exposure based on ΔUV254 or ΔTF was also proposed.