Local recurrence of cancer after surgery has long been a tough problem. In the present study, thermosensitive gel-based chemophotothermal therapy was applied to prevent the recurrence of liver cancer after surgery. Mesoporous silica nanoparticles (MSNs) were used as first-level carrier to co-load doxorubicin (DOX) and ICG. Then, the drug-loaded MSNs (D-I@MSN) were incorporated into poloxamer gel. A mimic model of liver cancer recurrence after surgery was prepared by subcutaneously injecting H22 cells into the armpit of mice. Then the two-level composite gel (D-I@MSN/gel) was also subcutaneously injected at the same site before the formation of tumor, followed by 808 nm laser irradiation. The loading efficiency and entrapment efficiency of DOX were as high as 8.85% and 96.9%, and that of ICG were 9.24% and 99.3%, respectively. The results of in vitro cytotoxicity showed that cell viability in D-I@MSN+Laser group was only 5.8% after being irradiated by 808 nm laser for 5 minutes (0.5 W/cm2 ). In animal studies, tumor formation (tumor recurrence) was greatly inhibited in D-I@MSN+Laser group. The thermosensitive gel-based chemophotothermal therapy showed excellent safety and efficacy when applied in the prevention of mimic local tumor replase after surgery in mice, presenting its great potential clinically. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.