This paper uses a unique firm-level data set from China’s two most developed regions, the Yangtze River Delta (YRD) and the Pearl River Delta (PRD), to examine the effects of environmental regulations on innovation. Variations in air and water pollution reduction plans under the Total Emissions Control Policy from the 10th to the 12th Five-Year Plans (2001–2015) are explored to measure the stringency of environmental regulations faced by industrial firms. To alleviate endogeneity concerns, we calculate city-level fair pollution reduction volumes which rely only on each city’s contribution to national pollution emissions in the base years and use them as instrumental variables of reduction plans. The two-stage least square estimations reveal that while air pollution regulation (APR) motivates industrial firms to innovate, water pollution regulation (WPR) hinders firm innovation. We confirm the opposite effects by estimating the impact on entrepreneurs’ perceptions of the importance of innovation in industrial firms’ development. Heterogeneity effect analysis shows that APR also hinders innovation in heavily air-polluting industries and state-owned firms, and WPR produces a decreasing innovation-hindering effect over time, which is larger in the YRD region than in the PRD region. We interpret the opposite impacts with the fact that water pollution discharges are more equally distributed across industries than air pollution emissions, resulting in more pervasive and stringent WPR.