NLRs are important intracellular pattern recognition receptors and play an essential role in innate immunity for vertebrates. However, research on sturgeon NLRs is still scarce. In this study, the NLRC3-like gene from Siberian sturgeon (Acipenser baerii) (AbNLRC3-like) was cloned and characterized. The AbNLRC3-like full-length cDNA was composed of 3310 bp with a 166 bp of 5′-UTR, 2838 bp open reading frame (ORF) and 306 bp 3′-UTR, encoding 945 amino acids. Structural analysis of AbNLRC3-like showed the typical NLRs structure, including a central NACHT domain and a C-terminal 12 LRR motifs. Quantitative real-time PCR (qRT-PCR) analysis revealed that AbNLRC3-like was widely distributed in all tested tissues with a relatively high expression level in the mid-kidney, head-kidney and spleen. After Streptococcus iniae infection, the mRNA expression of AbNLRC3-like was significantly up-regulated at the pre-mortality period and the recovering period in valvula intestine, but it was significantly down-regulated around the mortality period in the duodenum and spleen. In splenic leukocyte, the mRNA expression of AbNLRC3-like was significantly induced by LPS, PGN and Poly(I:C). These results suggested that AbNLRC3-like may play a critical role in the immune response of Siberian sturgeon during pathogen challenge. To our best knowledge, this is the first report of the NLRC3 gene in sturgeon.