Chemo-photothermal combination therapy could achieve synergistically enhanced efficiency against tumors. Nanocarriers with good safety and high efficiency for chemo- photothermal therapy are pressingly needed. A new type of hydroxyethyl starch (HES) based on nanoparticles (NPs) loaded with doxorubicin (DOX) and indocyanine green (ICG) was, thus, developed in this study. DOX-loaded HES conjugates with redox-sensitivity (HES-SS-DOX) were first synthesized and they were then combined with ICG to self-assemble into HES-SS-DOX@ICG NPs with controlled compositions and sizes via collaborative interactions. The optimal HES-SS-DOX@ICG NPs had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. They were able to fast release the loaded DOX in response to the redox stimulus and the applied laser irradiation. Based on the H22-tumor-bearing mouse model, these NPs were found to tendentiously accumulate inside tumors in comparison to other major organs. The HES-SS-DOX@ICG NPs together with dose-designated laser irradiation were able to fully eradicate tumors with only one injection and one single subsequent laser irradiation on the tumor site during a 14-day treatment period. In addition, they showed almost no impairment to the body. The presently developed HES-SS-DOX@ICG NPs have good in vivo safety and highly efficient anti-tumor capability. These NPs in conjugation with laser irradiation have promising potential for chemo-photothermal cancer therapy in the clinic.