Canine distemper is a severe and lethal viral disease of dogs and wild carnivores with an urgent need for the identification of effective antiviral agents against canine distemper virus (CDV). We assessed multiple agents for their ability to block the replication of three different lineages of CDV isolated from wild carnivores in the United States. Six antiviral compounds were selected after preliminary experiments that excluded ribavirin, hesperidin and rutin: a protease inhibitor (nirmatrelvir), a polymerase inhibitor (favipiravir) and four nucleoside analogs (remdesivir, GS-441524, EIDD2801 and EIDD1931). Antiviral efficacy was determined by the attenuation of the cytopathic effect in a CDV-susceptible cell line and the inhibition of viral RNA replication. The nucleoside analog GS-441524 effectively blocked the replication of CDV at pharmacologically relevant concentrations. Four other antiviral agents inhibited CDV replication to a lesser degree (remdesivir, nirmatrelvir, EIDD2801 and EIDD1931). The replication of different viral lineages was differentially inhibited by the antivirals. Several of the nucleoside analogs have been safely used previously in carnivore species for the treatment of other viral diseases, suggesting that they may be promising candidates for the treatment of canine distemper in dogs. Our results emphasize the need to consider different viral lineages in the screening of antiviral compounds.