This study employs the comprehensive index method and the coefficient of variation method to explore the integration mechanism of regional culture and tourism. It measures the integration development degree of culture and tourism subsystems in 16 prefecture-level cities in Anhui Province. Additionally, the decision-making trial and evaluation laboratory (DEMATEL) method is used to investigate the integration mechanism. The results indicate the following: From 2012 to 2021, the comprehensive index, integration degree, and integration development degree of cultural subsystems in the 16 prefecture-level cities in Anhui Province exhibited noticeable periodic changes. Between 2015 and 2019, the growth rate in eastern prefecture-level cities was significantly faster than that in central and western cities. In 2019, all regions—eastern, central, and western—experienced a downward trend, and the spatial difference in recovery growth in 2020 was minimal. Within the cultural and tourism integration system, the industry foundation and activity scale of the cultural subsystem are interdependent, while the industry foundation of the tourism subsystem results from the market scale. The central factors are primarily focused on the industrial base and the activity or market scale of the criterion layer of both subsystems. Conversely, the economic contribution of the criterion layer of the two subsystems has a minimal impact on centrality.