The refractory lead oxide ore has become an important source of lead metal with the continuous depletion of lead sulfide minerals. Lead oxide ore is of poor floatability and there are few cases to concentrate it successfully. In this study, the sulfidization-xanthate flotation method is applied for the beneficiation of lead oxide ore in Yunnan Province (China) with sodium hexametaphosphate and carboxymethyl cellulose as depressant. Chemical analysis and phase analysis was performed to explore the physicochemical property of raw ore, which provides a research basis for process design and operational control. The main influencing factors during the process, including grinding fineness, reagent types, and dosage, etc., have been studied through flotation tests. Zeta potential measurements and Fourier transfer-infrared spectrometry (FTIR) analysis were conducted to reveal the function mechanism of the reagents. Based on the determined experimental conditions, open circuit tests and closed circuit tests with one stage rougher, three-stage scavenger, and two-stage cleaner flotation, were carried out with the run-of-mine ore with a lead grade of 4.57%. Through close circuit bench test, the lead concentrate with a lead grade of 64.08% and recovery of 92.30% was obtained. This study is of special value, as it provides referencing significance for economically exploiting lead oxide ore.