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© 2021 American Chemical Society.Gypsum (CaSO4·2H2O) with active catalytic performance was prepared from phosphorous rock through an improved clean wet process. The impact of the preparation conditions was extensively analyzed to identify the statistical significance toward the compositions of the prepared gypsum and catalytic performances during the transesterification reaction. The prepared catalyst predominantly contains CaSO4 (93%) with contaminations of silica (5%), P2O5 (0.25%), Fe2O3 (0.52%), Al2O3 (0.24%), and TiO2 (0.12%). Heavy–metal oxides, that is, Cr2O3, PbO, and CuO, were not detected from the prepared catalyst. The contaminants in gypsum are in the form of complicated composites such as SiO2, (Na2, K2)SiF6, MgF2, AlF3, Ca5(PO4)3F, and Ca3(PO4)2. The significant operational parameters, namely, the crystallization temperature and duration toward the catalytic performance, were identified by ANOVA. The BrÃśnsted acidic sites from the ionic S and O, which might be in the form of S–âO or SâO as the surface functional groups, attribute to transesterification catalysis. The theoretical simulation suggests that different ionic sulfates might co–exist on the surface of crystallite gypsum. The transport of reagents to the surface of catalytic sites also plays an important role under the investigated experimental conditions. The reusability study indicates an approximate 10% deactivation after the reaction.