Environmental degradation and the proliferation of non-native fish species threaten the endemic, and highly unique fish faunas of the American Southwest. The present study examines long-term trends (> 160 years) of fish species distributions in the Lower Colorado River Basin and identifies those native species (n = 28) exhibiting the greatest rates of decline and those non-native species (n = 48) exhibiting the highest rates of spread. Among the fastest expanding invaders in the basin are red shiner (Cyprinella lutrensis), fathead minnow (Pimephales promelas), green sunfish (Lepomis cyanellus), largemouth bass (Micropterus salmoides), western mosquitofish (Gambussia affinis) and channel catfish (Ictalurus punctatus); species considered to be the most invasive in terms of their negative impacts on native fish communities. Interestingly, non-native species that have been recently introduced (1950+) have generally spread at substantially lower rates as compared to species introduced prior to this time (especially from 1920 to 1950), likely reflecting reductions in human-aided spread of species. We found general agreement between patterns of species decline and extant distribution sizes and official listing status under the U.S. Endangered Species Act. ‘Endangered’ species have generally experienced greater declines and have smaller present-day distributions compared to ‘threatened’ species, which in turn have shown greater declines and smaller distributions than those species not currently listed. A number of notable exceptions did exist, however, and these may provide critical information to help guide the future listing of species (i.e., identification of candidates) and the upgrading or downgrading of current listed species that are endemic to the Lower Colorado River Basin. The strong correlation between probability estimates of local extirpation and patterns of native species decline and present-day distributions suggest a possible proactive conservation strategy of implementing management actions for declining species prior to extreme rarity and imperilment.