Water is life for all living organisms on earth, and all human beings need water for every socio-economic activity in their daily lives. However, constant challenges are faced in securing quality water resources due to environmental pollution, a growing demand, and climate changes. To overcome imminent worldwide challenges on water resources, desalination of seawater and saline wastewater became inevitable, and significant efforts have been deployed by the desalination research community to advance the technology. However, there is still a gap to take it to a higher sustainability and compatibility compared to conventional water treatment technologies. Among all efforts, the hybridization of two or more processes stands among the promising solutions for sustainable desalination, which synergizes benefits of multiple technologies. To evaluate the sustainability of hybrid desalination technologies, two different systems, namely; (i) multi-effect distillation – adsorption (MED-AD) and (ii) forward osmosis – membrane distillation (FO-MD), are investigated in this study. The method developed for the analysis of primary energy consumption in complex desalination systems is used to evaluate the performance of the MED-AD pilot facility at King Abdullah University of Science and Technology (KAUST). Results of the MED-AD pilot operation showed an improvement in water production with a higher energy efficiency under the same operating conditions (near the ambient temperature with the solar thermal system). For the FO-MD hybrid system, an investigation is carried out on a novel in-house integrated module and a comparative analysis with the conventional module is provided. An isolation barrier carefully placed in the novel design enhanced the hybrid performance by reducing both concentration and temperature polarization. In addition, the FO-MD hybrid process is evaluated for brine reclamation application in a SWRO-MD-FO system. The sustainability of the proposed system and the potential of a flexible sustainable operation are presented with the experimental study with real seawater and brine from the full-scale desalination plant.