Efficient utilization of waste heat to run a power and desalination systems is a key technology to mitigate the energy-water crisis. Organic Rankine Cycle (ORC) is one of the promising systems that can exploit low-grade waste heat. So, this paper introduces a novel ORC-based poly-generation system driven by waste heat to produce electrical, cooling, and heating power. The poly-generation system is integrated with multi-effect desalination (MED) system for freshwater production as well. Energy, exergy, and exergo-economic (3E) investigations are made to assess the feasibility of integration of the proposed novel ORC to MED cycle. The new ORC has an adjustable three-way valve to control the seasonal requirement of electrical, heating, and cooling power. Performance of the suggested multi-generation ORC/MED is evaluated by calculating the plant electrical efficiency (eta(elec)), energy utilization factor (EUF), overall exergy efficiency (eta(ex)), total product unit cost (c(p,tot)), electricity cost (C-elec), total water price (TWP), and exergo-economic factor (fk). It is found that the base case of the proposed multi-generation ORC/MED plant could produce electrical power of 8.055 MW at a cost of 1.035 (sic)/kWh, cooling power of 5.239 MW, heating power of 7.579 MW, and freshwater of 66.55 m(3)/h for 0.4136 $/m(3). While the eta(elec), EUF, eta(ex), andcp,tot are 13.38%, 53.27%, 37.22%, and 2.877 $/GJ, respectively. The parametric study indicates that adjusting the ratio of electric power generation to cooling power production has a significant impact on the thermo-economic efficiency of the ORC/MED plant and does not have any effect on the freshwater production. The multi-objective optimization analyses show that the electrical power, cooling power and EUF of the optimized case improve by 16%, 306.6% and 50%, respectively, and the cp,tot and Celec decrease by 16% and 9.5%, respectively.