Purpose <p>Insulin-like growth factor-1 (IGF-1) may play a role in breast cancer (BC) development. Metformin was found to exert anti-cancer function in several studies, partly by interference with the IGF-1 signaling pathway and reducing its blood levels. Therefore, our study aimed primarily to find out how metformin affected both IGF-1 levels and clinical outcomes in metastatic breast cancer patients (MBC) and secondarily to identify the correlation between post-treatment IGF-1 decline rates and BC prognosis and metastasis.</p> Methods <p>Fifty MBC female patients were randomly assigned to either the control group (who were administered conventional chemotherapy) and the intervention group (treated with metformin plus chemotherapy). An enzyme-linked immunosorbent assay (ELISA) was used to detect IGF-1 levels at baseline and three months post-treatment.</p> Results <p>IGF-1 levels in the metformin group were significantly lower than in the control group (<i>p</i> = 0.011). Furthermore, the percentage of post-treatment drop in IGF-1 levels differed significantly between the control and metformin groups (<i>p</i> = 0.001). Patients whose IGF-1 levels increased after treatment had a statistically significant occurrence of progressive disease (disease progression) in the control group higher than in the metformin group (92.9% versus 87.5%).</p> Conclusion <p>The co-administration of metformin with chemotherapy significantly inhibited the IGF-1 signaling pathway, which reduced progressive diseases and reduced mortality in non-diabetic MBC patients. However, while metformin exerts a robust IGF-1 lowering effect, combination chemotherapy and low metastasis burden may further enhance this effect.</p> Trail registration <p> Our trial was registered at clinicaltrials.gov (ID no. NCT04143282).</p>