Cancer is one of those leading diseases worldwide, which takes millions of lives every year. Researchers are continuously looking for specific approaches to eradicate the deadly disease, ensuring minimal adverse effects along with more therapeutic significance. Targeting of different aberrantly regulated signaling pathways, involved in cancer, is surely one of the revolutionary chemotherapeutic approach. In this instance, GSK3 and PI3K signaling cascades are considered as important role player for both the oncogenic activation and inactivation which further leads to cancer proliferation and metastasis. In this review, we have discussed the potential role of GSK3 and PI3K signaling in cancer, and we further established the crosstalk between PI3K and GSK3 signaling, through showcasing their cross activation, cross inhibition and convergence pathways in association with cancer. We also exhibited the effect of GSK3 on the efficacy of PI3K inhibitors to overcome the drug resistance and preventing the cell proliferation, metastasis in a combinatorial way with GSK3 inhibitors for a better treatment strategy in clinical settings.