The San Andres Formation, characterized by massive sulfate cementation (with ∼10%–30% of rock volume), is one of the most productive units in the Permian Basin. However, little attention has been paid to anhydrites, which affected the San Andres reservoir quality. Coupling petrography with geochemical analysis, this study aims at providing a holistic diagenetic framework in the Seminole San Andres Formation. Advanced evaporation of seawater has resulted in abundant bedded and nodular anhydrite precipitation along with reflux dolomitization. An early stage of bacterial sulfate reduction may have occurred and resulted in pyrite replaced anhydrite nodules. A small downward decreasing of δ13C in carbonates may be caused by either the secular carbon isotopic change of seawater or the consequence of bacterial sulfate reduction. Fluid inclusion data obtained from anhydrite cements suggest that (1) anhydrite cementation continued to the maximum burial temperature of ∼75°C and (2) a regional hydrothermal fluid activity with temperatures between 100°C and 128°C has occurred. Neogene meteoric water from the western uplifted mountain region may have promoted a late-stage bacterial sulfate reduction that caused anhydrite and dolomite dissolution and increased present-day reservoir quality in the residual oil zones. This study emphasizes the dynamics of anhydrite subjected to diagenesis that could result in an improved reservoir quality with greater heterogeneity in a mixed carbonate and evaporite system.