Many ecosystems have been invaded by more than one non-native species, but research evaluating the combined effects of multiple invasive species has been limited. In the southwest USA, many aquatic systems have been invaded by multiple species such as non-native crayfish and non-native fishes. We used experimental mesocosms to test individual and combined effects of invasive Red Swamp Crayfish, Procambarus clarkii , and Western Mosquitofish, Gambusia affinis , on endangered Pahrump Poolfish, Empetrichthys latos. We found that crayfish alone reduced adult poolfish survival, however crayfish did not limit production of poolfish juveniles. By contrast, mosquitofish had no effect on survival of poolfish adults, but significantly reduced recruitment of juveniles. When both crayfish and mosquitofish were present, both adult survival and juvenile production were significantly decreased. These findings were consistent with the recent decline of a wild poolfish population from over 10,000 fish to less than 1,000 poolfish following the establishment of crayfish and mosquitofish. This study demonstrates that conservation management of the Pahrump Poolfish must have active management and removal of invasive species, otherwise extirpation and eventually extinction will likely occur and provides an example for the compounding effects of multiple invasive species for other study systems.