Aiming to the personalized laser therapy of nevus of Ota (NO), a local thermal non-equilibrium model was employed to optimize laser wavelength, pulse duration, and energy density under different melanin depth and volume fraction. According to our simulation, the optimal pulse duration is between 15 and 150ns to limit heat transfer inside the hyperplastic melanin, and 50ns is recommended to decrease the energy absorption by normal melanin in epidermis. Correlations of the minimum and the maximum energy densities are proposed with respect to melanin depth and volume fraction for the 755-nm and 1064-nm lasers. For the same NO type, the therapy window of the 755-nm laser is larger than that of 1064-nm. For NO with shallow depth or low volume fraction, the 755-nm laser is recommended to make the treatment more stable owing to its lager therapy window. For deeper depth or higher volume fraction, the 1064-nm laser is recommended to avoid thermal damage of epidermis. Through comparison with clinical data, the optimized laser parameters are proved practicable since high cure rate can be achieved when energy density falls into the range of predicted therapy window. With developing of non-invasive measurement technology of melanin content and distribution, personalized treatment of NO maybe possible in the near future.