Fly oil shale ash (FOSA) is a waste material known for its pozzolanic activity. This study intends to investigate the optimum thermal treatment conditions to use FOSA efficiently as a cement replacement material. FOSA samples were burned in an electric oven for 2, 4, and 6 h at temperatures ranging from 550 °C to 1000 °C with 150 °C intervals. A total of 333 specimens out of 37 different mixes were prepared and tested with cement replacement ratios between 10 and 30. The investigated properties included the mineralogical characteristics, chemical elemental analysis, compressive strength, and strength activity index for mortar samples. The findings show that the content of SiO2 + Al2O3 + Fe2O3 was less than 70 in all samples. The strength activity index of the raw FOSA at 56 days exceeded 75. Among all specimens, the calcined samples for 2 h demonstrated the highest pozzolanic activity and compressive strength with a 75 strength activity index. The model developed by RSM is suitable for the interpretation of FOSA in the cementitious matrix with high degrees of correlation above 85. The optimal compressive strength was achieved at a 30 replacement level, a temperature of 700 °C for 2 h, and after 56 days of curing. © 2022 by the authors.