<p>The use of abandoned gypsum mines for oil reserves offers a sustainable solution for repurposing underground spaces. The mechanical properties of gypsum rock and the quality of stored oil are kay factors in determining the feasibility of crude oil storage in such environment. This study selected gypsum rock from Dawenkou gypsum mine (China) to investigate the water–rock/oil–rock interactions, focusing on the effects of water, H⁺/OH⁻ ions, Cl⁻ ions, and crude oil on both the mechanical strength and microstructures of the rock. The phase transformation of anhydrite to gypsum in the presence of water can cause a volume expansion, potentially leading to microcracks formation and reduced mechanical integrity. The results indicate that the acidic/alkaline environment and aggressive Cl⁻ ions significantly decrease the mechanical strength of gypsum, primarily due to mineral dissolution/pore generation. In addition, our EDS results indicate that mineral surfaces are coated by an oil film, thus potentially reducing friction between mineral grains and decreasing the strength of gypsum rock. Moreover, gas chromatography–mass spectrometry (GC–MS) was applied to quantitatively analyse the chemical composition of crude oil following short-term interactions with gypsum rock. A slight decrease in the pristane/phytane (Pr/Ph) ratio suggests that evaporation should be minimized during oil storage. These findings provide valuable insights into water/oil–rock interactions under various conditions, helping engineers optimise the design of mine-out spaces and take preventive measures to protect stored crude oil from adverse water/oil interaction effects.</p>