Some time-temperature constraints are required to reconstruct the thermal history reconstructed by paleothermal indicators. The time-domain constraints limit the accuracy of the thermal histories. During the deformation process of the fold-and-thrust belt, differential horizontal slip occurs simultaneously with the uplift and cooling of the strata, resulting in differences in the uplift process. However, the thermal history, which revealed the cooling processes of the samples, did not consider the impact of flexural slip information, which has a significant effect on the structural analysis of a region with a long lateral slip distance. How to set appropriate time constraints to reconstruct the thermal history and accurately reveal the tectonothermal evolution of the fold-and-thrust belt is a scientific challenge in the field of low-temperature thermochronology research. In this study, a new thermo-kinematic approach that combines analog modeling, balanced reconstruction, various paleothermal indicators (low temperature thermochronology and maturity of organic matter) are used to constrain tectonothermal evolution of the eastern Sichuan fold-and-thrust belt, South China. This method accomplishes the fusion of “point-to-surface” and the quantitative coupling of overall-to-local analysis and meticulously dissecting the onset, pattern, rate, stage and size of uplift and exhumation during thrusting process. This study provides valuable insights regarding the restoration of tectonothermal evolution within the fold-and-thrust belt.