Background: The constitutively activated oncogenic signals of ERK, β-catenin, and signal transducer and activator of transcription-3 (STAT-3) are therapeutic targets in cancer treatment. The present study explored the anticancer mechanism of grape seed extract's polyphenolic compounds, Oligomeric-Proanthocyanidins (OPC-PACs), to combat oncogenic proliferative signaling crosstalk, as the precise mechanisms are not yet fully understood. Materials and Methods: The mechanistic anti-cancer effects of the OPC-PACs on oncogenic signaling crosstalk and apoptosis-induction were investigated, using liver and breast cancer cell lines (HepG2 and ZR-75-1), in vitro and by measuring tumor volume of MNU-induced mammary tumors, in vivo.  Results: Wst-1 assay demonstrated that the viability of OPC-PACs treated cells was significantly decreased in a concentration-dependent manner compared to the mock. The calculated IC₅₀ was (63.1 ± 0.024 mg/ml) and (61.6 ± 0.016 mg/ml) for HepG2 and ZR-75-1, respectively. Furthermore, OPC-PAC treatment for 48 h induced cell morphological changes, histone release, increased caspase-3 activity, and inhibition of p-ERK, β-catenin, and STAT-3 expression with apoptosis induction in HepG2 and ZR-75-1 cell lines as well as inhibition of tumor volume in vivo.   In vivo, OPC-PAC treatment for 45 days significantly (p < 0.05) decreased the tumor size of MNU-induced mammary tumors by 28.7% compared to untreated-induced tumors.  In-vivo cytotoxicity assessment confirmed the safety of the OPC-PACs treatment. Conclusion: The present study introduces OPC-PAC extract as a natural, non-toxic, and significantly inhibited crosstalk involved in cell proliferation that might act as a promising protective compound for consideration in complementary therapy in human cancers.