Ventilation optimization methods for highway tunnels using thermal potential difference in inclined shafts can enhance construction safety. Therefore, a case study is conducted on the  Zhongliangshan gas tunnel in Chongqing, China, using theoretical analyses and numerical simulations. First, the influence of the temperature difference inside and outside the tunnel and the thermal potential difference caused by inclined shaft slope on tunnel ventilation is examined. The pressure differences caused by the thermal potential difference in summer and winter are calculated, and the flow trend of natural wind in the inclined shaft is analyzed accordingly. Then, a numerical model is established to simulate the distributions of wind speed, wind direction, ventilation blind zones, and gas concentration in the tunnel under different working conditions. The research results show the following: (1) The thermal potential difference considerably affect the ventilation performance in tunnel. (2) In summer, the natural wind caused by the thermal potential difference conflicts with the wind direction of the jet fan, leading to formation of ventilation blind zones and reduction in ventilation efficiency, which is unfavorable for gas discharge. Based on such results, a ventilation optimization scheme combining natural wind and mechanical ventilation is proposed. This scheme makes full use of the thermal potential difference of the inclined shaft for ventilation, significantly improving wind speed and ventilation efficiency. After optimization, the wind speed in the inclined shaft increases with increasing thermal potential difference; the overall average wind speed in tunnel increases subsequently, reducing the ventilation blind zones and the average gas concentration, thus significantly improving the safety of the construction gas tunnel.