Feline coronavirus (FCoV) and feline calicivirus (FCV) commonly infect domestic cats, and are an important cause of morbidity and mortality. There are currently no effective antiviral agents for these pathogens. Studies reported herein attempt address this therapeutic shortfall through the testing of a panel of small molecule compounds and specifically designed small interfering RNAs (siRNAs) for antiviral effects against both viruses. Initial compound screening identified chloroquine, mefloquine, and hexamethylene amiloride as effective inhibitors of FCoV, whilst mefloquine effectively inhibited FCV. Efficacy at low micromolar concentration was confirmed with orthogonal testing, albeit with relatively narrow selective indices. Preliminary experiments performed to inform the antiviral mechanism of the compounds against FCoV demonstrated all three compounds acted at an early stage of viral replication. For FCV, mefloquine exhibited potent inhibition of a panel of recent field isolates and demonstrated additive effects in combination with recombinant feline interferon omega. For both FCoV and FCV, a number of siRNAs demonstrated potent and specific inhibition of viral replication. These were effective at low nanomolar concentrations, when used in combination, and against high viral loads. A structural siRNA variant, Dicer-substrate siRNA, demonstrated similar or better efficacy, depending on the target, over canonical siRNAs directed at the same FCoV motif. Limitations of antiviral siRNAs in terms of antiviral resistance were investigated. FCoV serially passaged through siRNA treated cells rapidly acquired resistance, however combination therapy with three siRNAs was able to delay this considerably. For FCV, siRNAs effective against the reference strain were broadly efficacious against field isolates, although some variability was noted. Taken together these results provide important information regarding potential antiviral therapies against these important pathogens.