Combination chemotherapy has become a treatment modality for breast cancer. However, serious side effects and high cytotoxicity associated with this combination therapy make it a high-risk method for breast cancer treatment. This study evaluated the anticancer effect of decorated niosomal nanocarriers loaded with cisplatin (CIS) and epirubicin (EPI) (on SKBR3 and 4T1 breast cancer cells) and on BALB/c mice. For this purpose, polyethylene glycol (PEG) and folic acid (FA) were employed to prepare a functionalized niosomal system to improve endocytosis. FA-PEGylated niosomes exhibited desired encapsulation efficiencies of ∼91.2 and 71.9% for CIS and EPI, respectively. Moreover, cellular assays disclosed that a CIS and EPI-loaded niosome (NCE) and FA-PEGylated niosomal CIS and EPI (FPNCE) enhanced the apoptosis rate and cell migration in SKBR3 and 4T1 cells compared to CIS, EPI, and their combination (CIS+EPI). For FPNCE and NCE groups, the expression levels of , , , and genes increased, whereas the expression of , , , and genes was downregulated. Histopathology results showed a reduction in the mitosis index, invasion, and pleomorphism in BALB/c inbred mice with NCE and FPNCE treatment. In this paper, for the first time, we report a niosomal nanocarrier functionalized with PEG and FA for codelivery of CIS and EPI to treat breast cancer. The results demonstrated that the codelivery of CIS and EPI through FA-PEGylated niosomes holds great potential for breast cancer treatment.