Spatially uneven urbanization shapes various urban-lake spatial patterns; however, the effect of pattern evolution on lake breeze front (LBF) penetration via thermal and aerodynamic mechanisms in inland multi-lake megacities remains unclear. Therefore, sensitivity experiments were conducted to examine LBF changes over the past 40 years in Wuhan, China—where lakes are located on the periphery of built-up areas or integrated with urban fabrics—using the Weather Research and Forecasting (WRF) model under high-temperature and weak-wind conditions. Moreover, we quantified the contributions of thermal (lake-land surface temperature differences (LSTD), urban heat island intensity (UHII)), and aerodynamic factors (lake-land surface roughness differences (LSRD)) to LBF penetration. The results showed that for lakes entirely within urban fabrics, the thermal and roughness characteristics at lake-land interfaces dominated LBF penetration. Specifically, urban expansion towards lakeshores without connections promoted LBF penetration due to the stronger positive benefits of the LSTD. However, urban expansion bordering lakeshores inhibited LBF penetration, as the inhibitory effects of LSRD outweighed those of LSTD. When lakes remained on the periphery of built-up areas, higher UHII and the UHII-weighted center moving towards suburban lakes accelerated the LBF movement into built-up areas. Based on these findings, we propose adaptive strategies for urban growth boundaries to facilitate the natural infiltration of LBFs into urban environments.