A series of six pharmaceuticals were degraded by continuous wave (CW) and pulsed wave (PW) ultrasound at 205 kHz using deionized water, wastewater effluent, and its isolated organic matter matrices. In deionized water, we observed that hydrophobicity is superior to diffusivity (D W) for predicting degradation kinetics. Enhancements in degradation kinetics by the PW mode were greatest for the highest D W (i.e., fluorouracil (5-FU)) and K OW (i.e., lovastatin (LOVS)) compounds, indicating that a pharmaceutical with either high diffusivity and low hydrophobicity or low diffusivity and high hydrophobicity benefits from additional time to populate the bubble–water interface during the silent cycle of PW ultrasound. Degradation of 5-FU and LOVS were inhibited by wastewater effluent to a greater extent than the other pharmaceuticals. In addition, a pulse enhancement (PE) for 5-FU and LOVS was not present in wastewater effluent. Irradiating 5-FU and LOVS in hydrophobic (HPO), transphilic (TPI), and hydrophilic (HPI) fractions of effluent organic matter (EfOM) showed that the TPI fraction reduced the PE the most, followed by the HPI and HPO fractions. The smaller size of the TPI over the HPO fraction and higher hydrophobicity of TPI over HPI implicate both size and hydrophobicity of EfOM in hindering degradation of pharmaceuticals.