Seawater represents a potential resource to ensure sustainable availability of water for population and irrigation purposes, especially in some areas of the world. Desalination processes allow the production of fresh water, but they generate also brine as waste product. Sustainable brine management should be identified to ensure proper disposal and potentially resource recovery. This experimental study showed that emerging technologies such as Microbial Desalination Cells (MDCs) may provide a valuable contribution to the sustainability of the seawater desalination sector. In this paper, we report results on lab-scale desalination brine treatments applying MDCs, which allow energy savings, resource recovery, environmental impact minimization, and reduction of the organic load in municipal wastewater. Our results showed that MDCs’ treatment allows the removal of approximately 33 g of salts (62% of the total)—including chlorides, bromides, and sulphates—from 20 mL of brine within 96 h. The MDCs, according to the source of energy and the presence of mature biofilm at the anode, spent 7.2 J, 7.9 J, and 9.6 J in the desalination process, with the higher amount of energy required by the abiotic system and the lesser by the MDCs fed with just wastewater. Our approach also showed environmental and energy reductions because of potential metal recovery instead of returning them into marine environment. We quantified the avoided life cycle of human and marine eco-toxicity impacts as well as the reduction of cumulative energy demand of recovered metals. The main benefit in terms of avoided toxicity would arise from the mercury and copper recovery, while potential economic advantages would derive from the recovered cobalt that represents a strategic resource for many products such as battery storage systems.