Background & Objectives: There is growing evidence to implicate the insulin/IGF-1R/PI3K/Akt signaling cascade in breast cancer development and the central role of aldose reductase (AR) in mediating the crosstalk between this pathway and angiogenesis. The current study was designed to investigate whether nimbolide, a neem limonoid, targets this oncogenic signaling network to prevent angiogenesis in breast cancer. Methods: Breast cancer cells (MCF-7, MDA-MB-231), EAhy926 endothelial cells, MDA-MB-231 xenografted nude mice, and tumour tissues from breast cancer patients were used for the study. Expression of AR and key players in IGF-1/PI3K/Akt signaling and angiogenesis was evaluated by qRT-PCR, immunoblotting, and immunohistochemistry. Molecular docking and simulation, overexpression, and knockdown experiments were performed to determine whether nimbolide targets AR and IGF-1R Results: Nimbolide inhibited AR with consequent blockade of the IGF-1/PI3K/Akt and HIF-1/VEGF signaling circuit by influencing the phosphorylation and intracellular localisation of key signaling molecules. Downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. Coadministration of nimbolide with metformin and the chemotherapeutic drugs tamoxifen/cisplatin displayed higher efficacy than single agents in inhibiting IGF-1/PI3K/Akt/AR signaling. Grade-wise increases in IGF-1R and AR expression in breast cancer tissues underscore their value as biomarkers of progression. Conclusions: This study provides evidence for the anticancer effects of nimbolide in cellular and mouse models of breast cancer besides providing leads for new drug combinations. It has also opened up avenues for investigating potential molecules such as AR for therapeutic targeting of cancer.