Cell membranes always respond to electric fields because cell membranes consist of ions and molecules. For many years, the technique of inducing electric pulses into the cell to increase its permeability has been investigated. When rectangular pulses with a train of high voltage (about 1000 V/cm) and low repetition frequency (about 1 Hz) are applied, patients feel an unpleasant sensation, while electroporation (EP) using higher repetition frequency and low voltage (HFLV) has been shown to have a higher inhibition of tumor growth. The current study aimed to predict synergism between EP and Bleomycin (SEPB) affecting K562 and MIA-PACA2 cancer cells and to optimize repetition frequency and electric pulse amplitude for HFLV EP by sampling a wide variety of different sets of pulse specifications on SEPB. Both cell types were exposed to higher frequency (4–6 kHz) and low voltage (50–150 V/cm). The characteristics of electric pulses that generate effective synergism with a small dose of Bleomycin were determined. As an output of the applied electric pulses with arbitrary frequency and voltage, the resulting synergism can be achieved using a theoretical model based on an adaptive neuro-fuzzy inference system (ANFIS). Results showed a significant correlation between experimentally observed and theoretically predicted data regarding the calculated coefficient of determination (R2 = 0.99 for K562 and 0.86 for the MIA-PACA2 cell type). It is concluded that this model is intensely reliable for prediction. This suggests that the model is valid and can calculate the SEPB that is affected by the magnitude of the electric pulse and the repetition frequency. Applying the prior experimental results to future drug delivery or biophysical applications might suggest this approach as a time and resource-saving alternative to conducting more tests.