“Innovation driven” is the proper term for promoting regional sustainable development under the general goal of national high-quality development. University–industry collaboration (UIC) has become an important innovation resource for regional sustainable development. The study aims to analyze the influencing factors and mediating mechanisms of university–industry collaboration scientific and technological (S&T) and business activities oriented for regional sustainable development in 30 provinces in China (excluding Tibet). Specifically, we used the partial least squares (PLS) structural equation modeling method to test the effects of innovation climate and resource endowments on regional sustainable development through two mode pathways of university–industry collaboration activities. The results show that the innovation climate and resource endowments significantly affect UIC in scientific and technological innovation activities, and then affect the regional economic development and human capital. UIC S&T innovation activities play positive mediating roles in promoting regional sustainable development. In addition, the innovation climate does not significantly impact the business activities of UIC. Therefore, region can get a greater sustainable development through UIC S&T innovation activities than business activities. Much more UIC S&T activities can improve the economic development, human capital, and environmental conditions in the region.