2´-5´-Oligoadenylate synthetase like protein (OASL) plays a key role in response to viral infections through selectively activating the OAS/RNase L or OASL/RIG-I signaling pathway.  Although classic pathway of OASL is well-known, its regulated genes or co-actors are largely unknown.  To study the possible molecular mechanism of duck OASL (dOASL), we performed RNA-sequencing (RNA-seq) and immunoprecipitation and mass spectrometry (IP-MS) at the level of mRNA and protein, respectively.  For RNA-seq, we used DF1 cell lines (DF1^dOASL+/+, DF1^{cOASL–/–,} and DF1) with or without the CK/0513 H5N1 virus (A/chicken/huabei/0513/2007) infection.  1 737 differentially expressed genes (DEGs) were identified as candidate target genes regulated by dOASL.  Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Weighted Correlation Network Analysis (WGCNA) were performed.  We identified one important yellow co-expression module correlated with antiviral immune response.  In this module, Ankyrin repeat and FYVE domain containing 1 (ANKFY1), harboring a BTB domain similar to the methyl CpG-binding protein 1 (MBD1) which bound to OASL in human, was regulated by dOASL.  At protein level, 133 host proteins were detected.  Interestingly, ANKFY1 was one of them binding to dOASL protein.  Further phylogenomic and chromosomal syntenic analysis demonstrated MBD1 was absent in birds, while mammals retained.  It is suggested that OASL-ANKFY1 interaction might act as a compensatory mechanism to regulate gene expression in birds.  Our findings will provide a useful resource for the molecular mechanism research of dOASL.