The global decline in amphibian diversity has become an international environmental problem with a multitude of possible causes. There is evidence that pesticides may play a role, yet few pesticides have been tested on amphibians. For example, Roundup is a globally common herbicide that is conventionally thought to be nonlethal to amphibians. However, Roundup has been tested on few amphibian species, with existing tests conducted mostly under laboratory conditions and on larval amphibians. Recent laboratory studies have indicated that Roundup may be highly lethal to North American tadpoles, but we need to determine whether this effect occurs under more natural conditions and in post-metamorphic amphibians. I assembled communities of three species of North American tadpoles in outdoor pond mesocosms that contained different types of soil (which can absorb the pesticide) and applied Roundup as a direct overspray. After three weeks, Roundup killed 96–100% of larval amphibians (regardless of soil presence). I then exposed three species of juvenile (post-metamorphic) anurans to a direct overspray of Roundup in laboratory containers. After one day, Roundup killed 68–86% of juvenile amphibians. These results suggest that Roundup, a compound designed to kill plants, can cause extremely high rates of mortality to amphibians that could lead to population declines.