Background: There is no doubt that one of the largest researcher dilemmas is cancer. Traditional therapeutic options such as chemotherapy, radiation, surgical and combinational treatment are widely accepted to cure or eradicate tumors. Despite chemotherapy being still a very potent weapon for cancer treatment, it is overwhelmingly associated with borders and serious side effects. There is consistently the probability of recurrence and these cancers can evolve resistance to chemotherapy and radiation treatments. Therefore, seeking a new therapeutic option of treatment is necessary to treat tumors accurately and prevent cancer metastasis. Objective: This work was directed at the evaluation of the efficacy of using activated Graviola nano-composite for leukemia targeted therapy. This work was conducted in vitro (two leukemia cell lines), and in vivo (90 leukemia induced mice). Laser and ultrasound were applied as an energy source. Material and methods: In this work, the biological effects of using activated Graviola nano-composite for leukemia targeted therapy were investigated through biophysical, biochemical, and hematological analysis. Results: The results revealed that Graviola nano-composite is a potential promising photo-sono sensitizer for cancer treatment and plays a critical role both in vitro and in vivo for inhibition and induction of cancer cell death. Conclusion: Our results revealed that activated Graviola nano-composite could be applied as a natural nano-sensitizer for sono-photodynamic therapy (SPDT) cancer targeting.