Despite the advanced treatment strategies, breast cancer remains the second cancer causing mortality across women worldwide. Notch signaling pathway has been found to be emerged in several cancers as well as in acquired and innate drug resistance. Therefore, understanding the role of Notch molecular mechanism could harbor beneficial impact to overcome chemoresistance and developing novel treatment strategies for cancer. Cisplatin (CIS) is an effective chemotherapeutic agent that is widely used against cancer but resistance is frequently occurs with limited therapeutic efficacy. One approach to overcome such unfavorable resistance is using complementary therapies with CIS. Thymoquinone (TQ) is a main compound in the essential oil of Nigella sativa. It has potent oncostatic activity by modulation of multiple regulatory pathways. Pentoxifylline (PTX) is a methylated xanthine derivative with remarkable anti-inflammatory and immunomodulatory actions. Combining TQ and PTX with CIS could be a promising strategy to suppress Notch signaling and overcome CIS resistance.