Mineral resource models have their accuracy highly dependent on data acquisition, which encompasses the entire project lifecycle, from exploration to post-mine closure. These data can include remote sensing, outcrop recognition, and samples from drilling, among other sources. The insights obtained through drilling represent the most straightforward and reliable method for comprehending the characteristics of subsurface mineral deposits, and decisions must be made to place drillholes efficiently. Traditionally, drilling strategies are defined by on-site geologists’ guidance based on experience and project requirements. However, the integration of mathematical models employing geostatistical methods has proven advantageous from numerous studies. Recently, these studies have gained popularity, mainly due to the increasing knowledge of the practitioners and growing computational power. The outcomes of these studies can be quite sensitive to many parameters, including variogram models, search strategies, and how the production scale is considered. Recognizing the absence of a one-size-fits-all solution, this paper emphasizes the significance of practitioner awareness of available options and parameter implications. Tailoring the approach to project maturity or substance type is also crucial. This work addresses two important questions in a mineral resource project: (1) determining the ideal drilling spacing according to metrics such as converted resources or uncertainty levels and (2) where to place additional drillholes to minimize uncertainty, thus increasing knowledge about the deposit. An integrated methodology is proposed, using ordinary kriging, geostatistical simulation, and simulated annealing, which can be applied throughout different phases of a mining project, from exploration to grade control. A real iron ore deposit in Brazil serves as a case study, illustrating the practical implementation of the integrated approach. The findings help choose drillhole spacing and minimize uncertainty in mineral resource projects, providing valuable guidance for industry practitioners.