The surrogate-based analysis and optimization of thermal damage in living biological tissue by laser irradiation are discussed in this paper. Latin Hypercube Sampling (LHS) and Response Surface Model (RSM) are applied to study the surrogate-based optimization of thermal damage in tissue using a generalized dual-phase lag model. Response value of high temperature as a function of input variables and the relationship of maximum temperature and thermal damage as a function of input variables are investigated. Comparisons of SBO model and simulation results for different sample sizes are examined. The results show that every input variable individually has quadratic response to the maximum temperature and maximum thermal damage in highly absorbing tissues.