Invasive species can have dramatic and detrimental effects on native species, and the magnitude of these effects can be mediated by a plethora of factors. One way to identify mediating factors is by comparing attributes of natural systems in species with heterogeneity of responses to the invasive species. This method first requires quantifying impacts in different habitats, ecosystems or geographic locations. We used a long-term, before-and-after study to quantify the impacts of the invasive and toxic cane toad (Rhinella marina) on two predators in a highly modified ecosystem: an irrigation channel in an agricultural landscape. Survey counts spanning 8 years indicated a severe population-level decline of 84 in Merten?s Water Monitor (Varanus mertensi) that was coincident with the arrival of cane toads. The impact of cane toads on V. mertensi was similar to that found in other studies in other habitats, suggesting that cane toads severely impact V. mertensi populations, regardless of habitat type or geographic location. In contrast, a decline was not detected in the Freshwater Crocodile (Crocodylus johnstoni). There is now clear evidence that some C. johnstoni populations are vulnerable to cane toads, while others are not. Our results reinforce the need for the replication of impact studies within and among species; predicting impacts based on single studies could lead to overgeneralizations and potential mismanagement.