Geochemistry and reactive transport play a critical role in many fields. In particular, calcite dissolution and precipitation are chemical processes occurring ubiquitously in the Earth’s subsurface. Therefore, understanding and quantifying them are necessary for various applications (e.g., water resources, reservoirs, geo-engineering). These fundamental geochemical processes can be monitored using the self-potential (SP) method, which is sensitive to pore space changes, water mineralization, and mineral–solution interactions. However, there is a lack of physics-based models linking geochemical processes to the SP response. Thus, in this study, we develop the first geochemical–geophysical fully coupled multi-species numerical workflow to predict the SP electrochemical response. This workflow is based on reactive transport simulation and the computation of a new expression for the electro-diffusive coupling for multiple ionic species. We apply this workflow to calcite dissolution and precipitation experiments, performed for this study and focused on SP monitoring alternating with sample electrical conductivity (EC) measurements. We carried out this experimental part on a column packed with calcite grains, equipped for multichannel SP and EC monitoring and subjected to alternating dissolution or precipitation conditions. From this combined experimental investigation and numerical analysis, the SP method shows clear responses related to ionic concentration gradients, well reproduced with electro-diffusive simulation, and no measurable electrokinetic coupling. This novel coupled approach allows us to determine and predict the location of the reactive zone. The workflow developed for this study opens new perspectives for SP applications to characterize biogeochemical processes in reactive porous media.