This work compares the sonochemical degradation of losartan and valsartan (antihypertensives) in water. Initially, the suitable operational conditions of ultrasonic power density and frequency were established. Under such conditions, losartan was eliminated in a higher percentage than valsartan, which was associated to differences in their hydrophobicities. Additionally, degradations in presence of isopropanol and ferrous ions confirmed that losartan was closer to cavitation bubble than valsartan. The structures of primary products indicated that sonogenerated hydroxyl radical attacked biphenyl tetrazole moiety (common nucleus of both pharmaceuticals). Then, theoretical calculations were applied to the products to estimate the toxicity, degree of oxidation and probable routes of aerobic biodegradation suggesting a beneficial action of sonodegradation. Finally, the sonochemical degradation of the antihypertensives was carried out in two simulated complex matrices (i.e., seawater and hospital wastewater) and an actual wastewater. Interestingly, the losartan and valsartan eliminations in such waters were similar to the observed in distilled water. This fact indicates the high potentiality of ultrasound to degrade losartan or valsartan in waters containing other substances, even at higher concentrations than these pollutants.