A combination of chemotherapeutic drugs and siRNA is emerging as a new modality for cancer therapy. A safe and effective carrier platform is needed for combination drug delivery. Here, a functionalized mixed micelle-based delivery system was developed for targeted co-delivery of methotrexate (MTX) and survivin siRNA. Linolenic acid (LA) was separately conjugated to branched polyethlenimine (b-PEI) and methoxy-polyethyleneglycol (mPEG). MTX was then conjugated to LA-modified b-PEI (MTX-bPEI-LA) to form a functionalized polymer-drug conjugate. Functionalized mixed micelles (M-MTX) were obtained by the self-assembly of MTX-bPEI-LA and LA-modified mPEG (mPEG-LA). M-MTX had a narrow particle size distribution and could successfully condense siRNA at an N/P ratio of 16/1. M-MTX/siRNA was selectively taken up by HeLa cells overexpressing the folate receptor (FR) and facilitated the release of the siRNA into the cytoplasm. In vitro, M-MTX/siRNA produced a synergy between MTX and survivin siRNA and markedly suppressed survivin protein expression. In tumor-bearing mice, M-MTX/Cy5-siRNA showed an elevated tumor uptake. In addition, M-MTX/siRNA inhibited tumor growth. Immunohistochemistry and a western blot analysis showed a significant target gene downregulation. In conclusion, M-MTX/siRNA was highly effective as a delivery system and may serve as a model for the targeted co-delivery of therapeutic agents.