Ampicillin and nafcillin antibiotics were treated by high frequency ultrasound (at 375 kHz and 24.4 W). Degradations followed pseudo-first order kinetics, which constants were k: 0.0323 min-1 for AMP and k: 0.0550 min-1 for NAF. Accumulation of sonogenerated hydrogen peroxide and inhibition degree of sonochemical removal (IDS) in presence of a radical scavenger were also stablished. Afterwards, ultrasound was combined with UVC light (sono-photolysis), with ferrous ion (sono-Fenton), and with ferrous ion plus UVC light (sono-photo-Fenton) to degrade the antibiotics. Furthermore, treatment of the pollutants in a complex matrix and removal of antimicrobial activity (AA) were considered. The antibiotics evolution was followed by HPLC-DAD technique and the accumulation of sonogenerated H2O2 was measured by an iodometry-spectrophotometry methodology (77.6 and 57.3 μmol L-1 of H2O2 after 30 min of sonication were accumulated in presence of AMP and NAF, respectively). IDS was analyzed through treatment of the antibiotics in presence of 2-propanol (87.1% for AMP and 56 % for NAF) and considering the hydrophobic character of pollutants (i.e., Log P values). Antimicrobial activity evolution was assessed by the Kirby-Bauer method using Staphylococcus aureus as indicator microorganism (sono-photo-Fenton process removed 100% of AA after 60 and 20 min for AMP and NAF, respectively). Finally, for degradations in the complex matrix, a simulated effluent of municipal wastewater treatment plant was utilized (sono-photo-Fenton led to degradations higher than 90 % at 60 min of treatment for both antibiotics). The data from the present work can be valuable for people researching on treatment of wastewaters containing antibiotics, application of advanced oxidation technologies and combination of sonochemical process with photochemical systems.