The objective of this work is to formulate a novel and physics-based nanomechanics framework to connect geochemical reactions in host rock to the resulting morphological changes at the microscopic lengthscale and to the resulting geomechanical changes at the macroscopic lengthscale. The key idea is to monitor the fraction of minerals based on their mechanical signature. We illustrate this procedure on the Mt. Simon sandstone from the Illinois Basin. To this end, various acidic fluid systems were applied to Mt. Simon sandstone specimens. The chemistry, morphology, microstructure, and mechanical characteristics were investigated across multiple lengthscales. Grid indentation was carried out with a total of 6900 individual indentation tests performed on 24 specimens. A good agreement was observed between the composition computed using statistical nanoindentation and measurements employing independent methods such as scanning electron microscopy, electron-dispersive X-ray spectroscopy, X-ray diffraction analyses, mercury intrusion porosimetry, flow perporometry, and helium pycnometry. An increase in porosity and a decrease in K-feldspar content were observed following the incubation in CO2-saturated brine, suggesting dissolution reactions involving feldspar. Thus, a rigorous methodology is presented to connect geochemical reactions and related compositional changes at the nano- and microscopic scales to alterations of the constitutive behavior at the macroscopic level.