We evaluated a physics-based model for planning for magnetic resonance-guided laser interstitial thermal therapy for focal brain lesions. Linear superposition of analytical point source solutions to the steady-state Pennes bioheat transfer equation simulates laser-induced heating in brain tissue. The line integral of the photon attenuation from the laser source enables computation of the laser interaction with heterogeneous tissue. Magnetic resonance thermometry data sets (n = 31) were used to calibrate and retrospectively validate the model’s thermal ablation prediction accuracy, which was quantified by the Dice similarity coefficient (DSC) between model-predicted and measured ablation regions (T > 57 °C). A Gaussian mixture model was used to identify independent tissue labels on pre-treatment anatomical magnetic resonance images. The tissue-dependent optical attenuation coefficients within these labels were calibrated using an interior point method that maximises DSC agreement with thermometry. The distribution of calibrated tissue properties formed a population model for our patient cohort. Model prediction accuracy was cross-validated using the population mean of the calibrated tissue properties. A homogeneous tissue model was used as a reference control. The median DSC values in cross-validation were 0.829 for the homogeneous model and 0.840 for the heterogeneous model. In cross-validation, the heterogeneous model produced a DSC higher than that produced by the homogeneous model in 23 of the 31 brain lesion ablations. Results of a paired, two-tailed Wilcoxon signed-rank test indicated that the performance improvement of the heterogeneous model over that of the homogeneous model was statistically significant (p < 0.01).