We use the panel data of innovation and entrepreneurship for global spatial autocorrelation and model selection testing. At the same time, we applied the Spatial Dubin Model (SDM) to empirically study the knowledge spillover effects of higher education campuses on regional innovation capabilities. Experimental research found that there are significant spatial differences in the innovation efficiency of universities. Specialized agglomeration can effectively improve the innovation efficiency and scale efficiency of colleges and universities. At the same time, the diversified agglomeration has no obvious effect on the innovation efficiency of colleges and universities. The accumulation of high-tech industries can effectively promote the innovation efficiency of universities. Human capital and opening to the outside world can effectively improve the innovation efficiency of universities.