Retinoblastoma (RB) is the most common ocular malignancy that occurs during childhood. Scavenger receptor class?A member?5 (SCARA5) is considered to function as an anti?oncogene in several types of malignant tumor. The present study investigated the functional role and underlying mechanism of SCARA5 in human RB cells. Reverse transcription?quantitative PCR and western blotting were used to detect the relative expression levels of SCARA5 in four human RB cell lines. In addition, transfection was performed to either knockdown or induce overexpression of SCARA5 in human RB?Y79?cells. The proliferation, migration and apoptosis of RB cells was then measured by Cell Counting Kit 8 assay, 5?ethynyl?2'?deoxyuridine assay, clone formation assay, Transwell assay, Hoechst staining and TUNEL staining, respectively. Western blotting was performed to detect changes in the expression levels of key proteins involved in the PI3K/AKT and apoptotic pathways. The present study revealed that SCARA5 was expressed at lower levels in four tumorigenic human RB cell lines compared with in a human retinal pigment non?tumorigenic cell line. Functional analysis demonstrated that overexpression of SCARA5 decreased the proliferation and migration, and promoted the apoptosis of human RB cells , whereas experiments revealed a decrease in RB progression following SCARA5 overexpression. In addition, overexpression of SCARA5 inhibited phosphorylated (p)?PI3K and p?AKT expression, and knockdown of SCARA5 increased p?PI3K and p?AKT expression; however, no changes in total PI3K and AKT expression were observed. Bcl?2 exhibited similar changes in expression to those displayed by p?PI3K and p?AKT, whereas Bax and cleaved caspase?3 exhibited trends in expression that were the opposite to those shown by p?PI3K and p?AKT. In conclusion, the present results demonstrated that SCARA5 could inhibit the proliferation and promote the apoptosis of RB cell lines by suppressing the PI3K/AKT signaling pathway, thus suggesting a novel strategy for treating RB.