This study was to investigate whether high-intensity interval training (HIIT) and saffron aqueous extract (SAE) would provide a synergistic effect to improve tumor volume reduction and also modulate pro- and anti-apoptotic protein expression in tumor tissue of 4T1 breast cancer-bearing mice. Female mice following induction of breast cancer through injection of 4T1 cell lines were randomly divided into four groups: (1) HIIT, (2) SAE, (3) HIITţ SAE, and (4) control. The tumor volume was significantly lower in the HIIT, SAE, and HIITţSAE groups than in the controls. The protein level of caspase-3 in the HIIT and the SAE groups was higher than in the control and the HIITţSAE groups. The Bax protein level in the SAE group was higher than in the control. The HIITţSAE group showed a lower level of Bax than the HIIT and the SAE groups. The protein level of Bcl-2 was higher in the HIITţSAE vs. both the HIIT and the SAE groups. Finally, the ratio of Bax/Bcl-2 was significantly higher in the HIIT and the SAE groups than in the HIITţSAE and control groups. These findings indicate that a combination of HIIT and SAE interventions does not improve the apoptotic induction in tumor tissue, while both HIIT and SAE treatments may mediate apoptotic pathway as evinced by the elevated ratio of Bax/Bcl-2 and caspase-3 levels during tumor progression in breast cancer-bearing mice.  Kulcsszavak: exercise, high-intensity interval training, Crocus Sativus L. extract, caspase-3, Bax/Bcl-2, apoptosis, breast cancer