In recent years, nano anti-cancer drugs have been of great importance in research for treating malignant tumors. Rosiglitazone regulates the proliferation and apoptosis of cancer cells. However, the role and mechanism of rosiglitazone gold nanoparticles in human retinoblastoma remains unclear. To investigate this, we treated retinoblastoma cells with different concentrations of rosiglitazone gold nanoparticles. We measured the proliferation and apoptosis of retinoblastoma cells via cell counting kit 8, flow cytometry, and western blotting for expression levels of peroxisome proliferator-activated receptor (PPAR)-gamma, phosphatidylinositol 3-kinase (PI3K), and Akt. Furthermore, PI3K inhibitors were used to explore whether rosiglitazone gold nanoparticles play a regulatory role through the PI3K/Akt pathway. Treatment with rosiglitazone gold nanoparticles significantly decreased the proliferation and apoptosis of retinoblastoma cells compared with untreated controls. Western blots showed that the nanoparticles significantly restrained activation of the PI3K/Akt pathway with the promotion of PPAR-gamma. Inhibition of the PI3K/Akt pathway significantly weakened the antitumor effect mediated by rosiglitazone gold nanoparticles. Thus, these nanoparticles display antitumor effects in human retinoblastoma cancer cells and play a regulatory role by restraining the activation of the PI3K/Akt signaling pathway.