Tyrosine kinase 2 (TYK2), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) all play critical roles in innate and acquired immunity.In this study, we investigated the association between the TYK2, JAK1, and STAT3 genes and genetic susceptibility to nonspecific digestive disorder (NSDD) in rabbits.Five coding single-nucleotide polymorphisms (cSNPs) in TYK2 were detected in New Zealand White (NZW) rabbits with direct sequencing, and two of them, c.1477 (C > T) and c.2013 (C > T), from two different linkage disequilibrium blocks, were further genotyped.A case control association analysis revealed that allele C (c.1477) in TYK2 increases the risk of NSDD (odds ratio [OR]: 1.21;95% confidence interval [CI] 1.036 2.145;P =0.021), whereas allele C (c.2013) plays a potentially protective role against NSDD (OR: 0.41;95% CI 0.2996 0.5705;P < 0.001).A gene gene interaction analysis with a multifactor dimensionality reduction (MDR) method indicated that the combination of c.1477 from TYK2 and c.831 from STAT3 is associated with the susceptibility to NSDD (OR: 7.2567;95% CI: 4.7306 11.1317;P < 0.0001).Together, our data demonstrate that the TYK2 gene is associated with NSDD in rabbits.The TYK2, JAK1, and STAT3 combination model may be used to assist breeders in selecting rabbits.