Improvisation of the contemporary water treatment technologies is critical not only to prevent water borne diseases but also to augment the available water sources. Here, a systematic study is effectuated to comprehend the upswing in the inactivation efficiency of Photo-Fenton (PF) chemistry induced by ultrasound (US) against antibiotic resistant (ABR) Acinetobacter baumannii (A. baumannii). Inactivation of A. baumannii (≈5×106 CFU/mL) was noticed within 75 and 105 min of US assisted PF (SPF) and PF processes respectively using 20 mg/L of H2O2 and 2 mg/L of Fe2+. It was interesting to notice that the PF reaction was effective under weak acidic condition (pH=3 and 5.5) whereas SPF process was realized over a wide pH range (3, 5.5, 7 and 9). No reactivation of the bacteria was found in both the processes till 96 h suggesting the impairment of not only the bacterial cell membrane but also the intracellular components. Experimental results although has suggested the generation of several reactive oxygen species (ROS), the inactivation mechanism was suggested to be dominated by the H2O2 and •OH. The damage caused to the bacterial cell membranes by the synergistic role of US and ROS was observed in the electron microscopy images. Comparative transcriptomic analysis has indicated the upregulation of genes regulating the LPS assembly proteins (Lpt A, B, C) and Pls B, Pgs A and Pal genes regulating the phospholipid synthesis which are known to regulate the stress induced response in bacteria. The SPF process was further validated with real water samples and the treated water was not found to have remarkable toxic effect on the in-vivo animal which endorse its candidature for future applications.