Efficient and selective extraction of lead was realized from the mixed sulfide-oxide lead and zinc ore by an in-situ self-reduction method for the first time. The thermodynamic feasibility of reaction scheme which consisted of reducing PbO2 from Zn leach residue containing PbO2 to PbSO4 by pyrite (FeS2) and sphalerite (ZnS) coexisted in the mixed ore in sulfuric acid (H2SO4) medium, followed by leaching PbSO4 as Pb(Ac)42− ions using NH4Ac solution, was elucidated. The effects of experimental parameters on extraction of Pb were comprehensively studied. Results demonstrated that the Pb extraction efficiency could achieve a high value of 99.4%, and specifically, the Pb(Ac)42− solution contained only Pb and Ca ions without any other impurity, which was conductive to preparing functional materials. This paper provides a novel pathway for selective and efficient extraction of Pb from the mixed ore.