Blasting cost prediction and optimization is of great importance and significance to achieve optimal fragmentation through controlling the adverse consequences of the blasting process. By gathering explosive data from six limestone mines in Iran, the present study aimed to develop a model to predict blasting cost, by gene expression programming method. The model presented a higher correlation coefficient (0.933) and a lower root mean square error (1088) comparing to the linear and nonlinear multivariate regression models. Based on the sensitivity analysis, spacing and ANFO value had the most and least impact on blasting cost, respectively. In addition to achieving blasting cost equation, the constraints such as fragmentation, fly rock, and back break were considered and analyzed by the gene expression programming method for blasting cost optimization. The results showed that the ANFO value was 9634 kg, hole diameter 76 mm, hole number 398, hole length 8.8 m, burden 2.8 m, spacing 3.4 m, hardness 3 Mhos, and uniaxial compressive strength 530 kg/cm2 as the blast design parameters, and blasting cost was obtained as 6072 Rials/ton, by taking into account all the constraints. Compared to the lowest blasting cost among the 146-research data (7157 Rials/ton), this cost led to a 15.2% reduction in the blasting cost and optimal control of the adverse consequences of the blasting process.