Recently, combination therapy has received much attention because of its highly therapeutic effect in various types of cancers. In particular, chemo-photodynamic combination therapy has been considered as an outstanding strategy. However, an abnormal increase in tumor angiogenesis caused by reactive oxygen species (ROS) generated during photodynamic therapy (PDT) has been reported. In this study, the complex of doxorubicin (DOX)-encapsulating anti-angiogenic small interfering RNA (siRNA) nanoparticle and chlorin e6 (Ce6)-encapsulating microbubble has been developed to suppress tumor angiogenesis. The first compartment, doxorubicin-encapsulating siRNA nanoparticle, was electrostatically coated using two biocompatible polymers to prevent the damage of genetic materials. The other part, Ce6-encapsulating microbubble, serves as an ultrasound-triggered local delivery system as well as a drug carrier. Both the in vitro and in vivo experimental results demonstrate successful inhibition of angiogenesis with a minimized damage of siRNAs caused by ROS as well as improved therapeutic effect by chemo-photodynamic-gene triple combination therapy using ultrasound-triggered local delivery. Doxorubicin-encapsulating anti-VEGF siRNA nanoparticle-Ce6-loaded microbubbles complex, DOX-siVEGF-NPs/Ce6-MBs, can simultaneously deliver the drug, photosensitizer and genetic material through sonoporation effect using external ultrasound irradiation. Chemo-photodynamic combination therapy significantly improved therapeutic effect. The genetic materials, anti-VEGF siRNA, placed separately with photosensitizer to avoid degradation by ROS, inhibit angiogenesis from side-effect of PDT. Display omitted