An investigation was conducted to examine the photothermal and thermomechanical effects of short-pulse laser irradiation on normal tissues. This study analyzed the impact of short-pulse laser radiation on the heat-affected region within tissues, taking into consideration a set of laser variables, namely wavelength, intensity, beam size, and exposure time. The beam size ranged between 0.5 and 3 mm, and the intensity of the laser radiation ranged from 1 to 5 W/mm2 at wavelengths of 532 and 800 nm. A three-layered, three-dimensional model was implemented and studied in a polar coordinate system (r = 10 mm, z = 12 mm) in COMSOL Multiphysics (version 5.4, COMSOL Inc., Stockholm, Sweden) to perform numerical simulations. The Pennes bioheat transfer model, Beer-Lambert, and Hooke’s law are integrated to simulate the coupled biophysics problem. Temperature and stress distributions resulting from laser radiation were produced and analyzed. The accuracy of the developed model was qualitatively verified by comparing temperature and mechanical variations following the variations of laser parameters with relevant studies. The results of Box-Behnken analysis showed that beam size (S) had no significant impact on the response variables, with p-values exceeding 0.05. Temperature (Tmax) demonstrates sensitivity to both beam intensity (I) and exposure time (T), jointly contributing to 89.6% of the observed variation. Conversely, while beam size (S) has no significant effect on stress value (Smax), wavelength (W), beam intensity (I), and exposure time (T) collectively account for 71.6% of the observed variation in Smax. It is recommended to use this model to obtain the optimal values of the laser treatment corresponding to tissue with specified dimensions and properties.