Environmental issues are raised from the global warming due to raised Carbon Dioxide (CO2) emissions of factories worldwide. Cement manufacturing is highly energy- and emissions-intensive because of the extreme heat required to produce it. Producing a ton of cement requires 4.7 million British Thermal Units (BTU) of energy, equivalent to about 400 pounds of coal, and generates nearly a ton of CO2. Therefore, it is necessary to reduce cement production; as a result, it contributes to solving those issues. This study investigates the effect of two major chemical compositions in the CKD and FA on the long-term compressive strength of cement mortar, especially their Calcium Oxide (CaO) and Silicon Dioxide (SiO2) contents; furthermore, their chemical, mineralogical, and microstructure are compared. In addition, 228 data for FA-modified cement mortar and 167 data for CKD-modified cement mortar were collected from previous literature and used to develop predictive models to forecast the compressive strength of cement mortar modified with CKD and FA. The dataset contained different mix proportions of the cement mortar, such as curing times, various SiO2 (%), CaO (%), water/cement ratio (w/c), and curing times up to 90 days. The result of the Multi expression programming (MEP), full quadratic (FQ), Nonlinear regression (NLR), and artificial neural network (ANN) models were used to quantify the effect of CaO and SiO2. The short-term compressive strength of cement mortar modified with fly ash (from 1 to 28 days) decreases with increasing the fly ash content, while the long-term compressive strength (from 28 to 90 days) increases by up to 15% replacement of cement with fly ash. However, the compressive strength of the cement kiln dust modified-cement mortar decreases with increasing the cement kiln dust content. The sensitivity evaluation discovered that the most influential parameter for predicting compressive of the cement mortar modified with CKD and modified with FA is the curing time.