Chlorine dioxide (ClO) has been used as a disinfectant in water treatment for a long time, and its use for micropollutant abatement in wastewater has recently been suggested. Surprisingly, a mechanistic understanding of ClO reactions in (waste)water matrices is largely lacking. The present study contributes to this mechanistic understanding by performing a detailed investigation of ClO reactions with organic matter using phenol as a surrogate for reactive phenolic moieties. A concept for indirectly determining HOCl using 2- and 4-bromophenol was developed. The reaction of phenol with ClO formed chlorite (62 ± 4% per ClO consumed) and hypochlorous acid (HOCl) (42 ± 3% per ClO consumed). The addition of ClO to wastewater (5 × 10 M ClO) resulted in 40% atenolol and 47% metoprolol transformation. The presence of the selective HOCl scavenger glycine largely diminished their transformation, indicating that atenolol and metoprolol were transformed by a fast reaction with HOCl (e.g., k (atenolol + HOCl) = 3.5 × 10 M s) that formed in ClO reactions with the wastewater matrix. The formation of HOCl may thus increase the number of transformable micropollutants in ClO applications. However, chlorine related byproducts may also be formed.