The degradation of diphenhydramine hydrochloride (DPH), via UV-vis/H2O2, Fenton, photo-Fenton and photocatalysis processes, was studied under different radiation sources. In addition, the Fenton and photo-Fenton processes at acid pH and circumneutral pH have been compared. The importance of the source of irradiation, UV-C (λ = 254 nm), black blue lamps (BLB, λ = 365 nm) and simulated solar radiation (SB, SolarBox), was investigated at lab-scale. Moreover, compound parabolic collectors (CPC), at pilot plant scale with sunlight, have been also applied in photocatalytic treatments. Photo-Fenton process employing black blue lamps gave the best DPH abatement (100% of DPH conversion at 10 min for acid pH and 20 min for circumneutral pH), using the highest Fe2+ (5 mg/L) and H2O2 (150 mg/L) concentrations at 50 mg/L of initial DPH concentration. Using Fenton, 100% of DPH conversion was reached at 30 min for both pHs tested. In the case of UV-C/H2O2, 100% of DPH elimination was achieved in 20 min using 150 mg/L of H2O2. In the photocatalytic process, using 0.4 g TiO2/L, after 60 min of irradiation, only 35.7% and 8.7% of DPH conversion have been obtained in SB and CPC, respectively. The DPH degradation in the photocatalytic process was greatly enhanced adding H2O2. In all the cases, increasing the H2O2 dose enhances the reaction rate due to higher OH[rad] production. However, not significant mineralization was obtained. The highest DPH mineralization was 36.8% and 38.5% of TOC reduction with photo-Fenton in BLB lamps using 150 mg/L of H2O2 and 2.5 mg/L of Fe2+, for acid pH and circumneutral pH, respectively. The major reaction intermediates these processes were identified by ionization/mass spectrometry and a DPH photo-degradation structures was proposed.