Tectono-geochemical data measured from tectonites host a wealth of information that is closely related to the accumulation and dispersion of ore-forming materials, while structure system is the only pathway to connect the deep orebody with the surficial tectono-geochemical anomaly, and both have correspondence and consistency. Based on the geological precondition that structure system and ore-forming process are closely associated with each other, the study proposed a method of sequential Gaussian co-simulation of tectono-geochemical anomaly, which integrates the tectono-geochemical anomaly with the ore-controlling structure system to solve two basic geological prospecting problems that are closely associated with ore-forming space and ore-forming material migration. A case study for concealed Pb–Zn prospecting based on tectono-geochemical data in the Huangzhuguang ore cluster (China) was employed to examine the potential applications of the proposed method. Firstly, centered logratio transformation was employed to remove the closure effect of tectono-geochemical data and to make the data conform to an approximate normal distribution. Secondly, sequential Gaussian co-simulation was applied to improve the simulation results of the tectono-geochemical anomaly by introducing the ore-controlling structure system. Thirdly, the probability distribution of tectono-geochemical anomalies was quantified by uncertainty modeling technique. The case study demonstrated that the proposed method can significantly improve the performance of the primary variable in predicting concealed ore deposits.