Global change transforms processes regulating carbon dioxide (CO2) concentrations in lakes, yet our understanding of the broad-scale responses of lake CO2 to global and local human perturbation across heterogeneous landscapes and multidecadal time scales is limited. We examined decadal variability in the carbon isotope (δ13C) composition of subfossil zooplankton (Branchiopoda: Cladocera) in seven large clear perialpine lakes, including three previously studied sites, to decipher different patterns in summer surface CO2 concentrations. Generalized additive models were used to examine whether and how these patterns connect to changing nutrient regimes and anthropogenic warming over the past century. In all but one of the lakes shifts in cladoceran δ13C values coincided with turning points in the eutrophication history, broadly implying decreasing summer surface CO2 concentrations driven by phosphorus fertilization of pelagic primary production. Yet where nutrient concentrations remained below mesotrophic levels, the positive relationship between δ13C and phosphorus diminished indicating that the strong biotic control of CO2 concentrations was overwritten, probably by catchment inorganic carbon inputs and internal biochemical processes. Even under extensive nutrient loading, the connection was further weakened in lakes with high catchment to lake area ratio attributable to increased catchment interference and shorter water residence times. Warming of the perialpine region was also imprinted in the isotope records, yet the temperature effects appeared modest and were restricted to three smaller lakes with lower drainage ratios. In these lakes, warming contributed to declining cladoceran δ13C values likely partially driven by epilimnetic deepening increasing CO2 in surface waters. Overall, our results manifest the broad heterogeneity of lake responses to global change and point to the importance of hydrogeomorphic context in shaping the sensitivity and responses of lake CO2 to changing nutrient regimes and warming at the regional scale.