Purpose <p>The oncogenic potential of pituitary tumor-transforming gene-1 (PTTG1) has been well-documented in multiple cancer types. This study explored the biological role and molecular mechanism of PTTG1 in retinoblastoma.</p> Methods <p>PTTG1 and c-myc expression levels were assessed through RT-qPCR and western blot analysis. Y79 and SO-RB-50 cells underwent PTTG1 knockdown or c-myc overexpression treatment. Cell proliferation was evaluated using CCK-8 assay and colony formation experiments. Flow cytometry was utilized to analyze cell cycle progression and apoptosis. Western blotting was performed to determine the expression of cell apoptosis and cell cycle-related proteins. Functional rescue experiments were conducted to investigate the impact of c-myc on the malignant behaviors of RB cells.</p> Results <p>PTTG1 expression was found to be upregulated in retinoblastoma tissues compared to normal retinal samples. Silencing of PTTG1 resulted in decreased proliferation and colony formation ability of retinoblastoma cells, as well as the induction of apoptosis and cell cycle arrest. Additionally, downregulation of PTTG1 led to inhibition of c-myc, resulting in reduced levels of cyclin A, cyclin D1, CDK2, and CDK4. The overexpression of c-myc reversed the effects caused by silencing PTTG1 on malignant behaviors of retinoblastoma cells.</p> Conclusions <p>PTTG1 promotes retinoblastoma cell proliferation and inhibits apoptosis via activating c-myc, which represents a potential value of PTTG1 for retinoblastoma treatment.</p>