The extraordinarily high salinity of seawater (e.g., Gulf seawater) requires a seawater desalination system such as two-pass reverse osmosis (RO). However, the auxiliary brackish water reverse osmosis (BWRO) treatment for satisfying the produced water quality significantly increases the energy consumption. This study first proposes a novel concept, integrating membrane capacitive deionization (MCDI) and reverse electrodialysis (RED) with RO to treat high-salinity seawater with enhanced energy efficiency. In this hybrid system, MCDI successfully substituted for BWRO and met the required water quality regulations by the World Health Organization (WHO). Moreover, RED recovered 33% of the energy from discharges. The optimum operating conditions of the RO-MCDI hybrid system were found to be 0.8 V of applied voltage on MCDI at 50% and 80% of water recovery for the first pass RO and the second pass MCDI, respectively. In particular, the great flexibility of MCDI in removal efficiency could generate notable synergistic effects with RED, which could lead to better energy efficiency. Consequently, under optimized operation conditions, the energy consumption of this novel RO-MCDI-RED hybrid system was respectively reduced by 39.0% and even 16.8% compared to that of a typical two-pass RO system without and with RED.