Channel catfish (Ictalurus punctatus) used in commercial aquaculture are raised in earthen ponds characterized by diel swings in dissolved oxygen concentration that may decrease to moderate or even severe levels of hypoxia. Low dissolved oxygen in catfish production ponds can suppress appetite, leading to suboptimal growth. To understand the underlying molecular framework that may govern appetite in channel catfish during hypoxia, the hypothalamus transcriptome was analyzed to identify differentially expressed genes (DEG) and patterns of genes responding to hypoxia. Channel catfish were subjected to 12 hours of hypoxia at 20% oxygen saturation (1.8 mg O2/L at 27 °C) followed by 12 hours of recovery in normoxic water (100.1% oxygen saturation; 8.0 O2/L) and fish were sampled at 0-, 6-, 12-, 18-, and 24-hour time points, with the hour 6 and 12 samplings occurring during hypoxia. Among all time points sampled, 190 genes were differentially expressed, with the greatest numbers found during the periods of hypoxia. The amount differentially expressed genes fell sharply during the normoxic recovery time points. Differentially expressed genes were grouped by function into Gene Ontology (GO) biological processes and were most overrepresented by the group “response to hypoxia” and GO molecular processes were predominated by “iron ion binding”. Gene expression patterns in the hypothalamus suggests an attempt to increase vascularization coupled with a shift to anaerobic glycolysis provides tissue-level protection from hypoxic damage. This work identified several gene candidates that could be useful targets for future studies investigating appetite, in addition to other potential biomarkers for hypoxia.