This paper addresses the applicability of liquid–liquid extraction for separating mineral particles by the difference in oil–water partition coefficient, for the seafloor mineral processing of seafloor massive sulfides (SMSs). Measurements of contact angle of sulfide mineral–aqueous solution–oil systems under high-pressure conditions were performed to evaluate the efficiency of liquid–liquid extraction at high pressures. The results showed that the contact angle stayed around 80–100 deg at the pressure range up to 16 MPa, and the changes in the contact angles were within 5 deg with varying pressure. Extraction experiments were carried out by using particles of an SMS ore, which contained Zinc (Zn), Lead (Pb), and Barium (Ba) in the grade of more than 10 mass% and Copper (Cu) in a small percentage, to evaluate the beneficiation performance of liquid–liquid extraction. In the experiments, extraction conditions such as the dosage of chemical reagents and pH in the aqueous solution were varied to optimize both the recovery and selectivity of Cu, Zn, and Pb in the oil phase and those of Ba in the water phase. The experimental results showed that the optimum condition was 200 g/t dosage—pH 7, where the grade and recovery were ca. 37 mass% and ca. 90 mass%, respectively. The beneficiation performance of liquid–liquid extraction would be comparable with that of flotation, adapted to the processing of other SMS ores.