The Tasmanian devil, an iconic Australian marsupial, has faced a severe threat in recent years in the form of a transmissible cancer. Devil facial tumour (DFT) disease kills over 90% of afflicted devils and there is currently no treatment. However, oncolytic virotherapies may unlock new solutions for tackling this disease. To assess susceptibility of DFTs to oncolytic therapies, we exposed devil cell lines to common human oncolytic agents, including two poxviruses and a type 1 herpes simplex virus. Surprisingly, only poxviruses preferentially grew in DFT cell lines when compared to healthy devil fibroblast cells – up to 100-fold higher. Rapid poxvirus penetration into 3D cultures was also observed via microscopy, where infection reached the centre of tumour spheroids in 2-3 days. Contrastingly, herpes simplex virions entered and expressed genes in DFT cells but were unable to produce viable progeny. To better understand our observations, transcriptomic analysis was performed on devil cells before and after poxvirus and herpesvirus infection. Various host factors required for herpes simplex virus replication were diminished in the tumour cells, whilst antiviral factors for poxviruses were also depleted. These may explain why poxviruses grew well, but herpes simplex grew poorly. Further, RNA sequencing revealed increased inflammatory signals in all infected DFT cells, signifying promotion of an inflammatory environment - a prerequisite for oncolytic viruses. These data suggest intratumoral administration of poxviruses would be a viable treatment for captured devils, a step-up from the current “release or cull” strategy. Oncolytic poxviruses could also bolster existing plans for prophylactic DFT vaccines, where devils could receive one or both vaccines to alleviate current tumours and protect against future ones. Overall, these oncolytic agents may provide insight into devil anti-tumour immunity and serve as an exciting new avenue for treating transmissible cancers in Australian wildlife.