<p>Nowadays, there is a specific need to develop environmentally sustainable desalination methods in light of the growing environmental issues and water scarcity. In this regard, membrane distillation (MD) is an evolving and highly promising technology that efficiently and sustainably distills without causing pollution especially since this technology can work with solar energy. VMD is among the most widely recognized configurations in MD technologies. However, the coupling with solar thermal and PV energy to power VMD has been relatively understudied, and very fewer studies have focused on energetic and economic efficiency of completely autonomous VMD plants. This research presents a thermo-economic optimization for an autonomous solar-powered VMD unit. The results proved that the energy performance of the process improves with augmenting inlet temperature and increasing vacuum level on the permeate side of the membrane. Furthermore, productivity and energy performance are significantly increased by raising membrane permeability and recycling rate. In addition, it has been noted that the rejection rate should not exceed 20% to maximize specific energy consumption (SEC). In addition, water production cost (WPC) is greatly decreased by higher supply temperatures. In terms of how feed velocity affects WPC, it was discovered that rising the feed flow has an impact on the capital cost and productivity. An optimal WPC of 16.46 $/m³ was attained with a feed flow rate of 3 m³/h, which corresponds to a feed velocity of 0.66&#xa0;m/s.</p>