Heat stress (HS) triggers oxidative stress, systemic inflammation, and disrupts growth efficiency of livestock. β-adrenergic agonists supplemented to ruminant livestock improve growth performance, increase skeletal muscle mass and decrease carcass fat. The objective of this study was to understand the independent and interacting effects of HS and zilpaterol hydrochloride (ZH) supplementation on the transcriptome of subcutaneous white adipose tissue and the longissimus dorsi muscle in steers. Twenty-four Red Angus-based steers were assigned to thermoneutral (TN; Temperature Humidity Index (THI)=68) or HS (THI=73-85) conditions and were not supplemented or supplemented with ZH (8.33 mg/kg/day) for 21 d in a 2x2 factorial. Steers in the TN condition were pair-fed to the average daily feed intake of HS steers. RNA was isolated from adipose tissue and skeletal muscle samples collected via biopsy on 3, 10, and 21 d and sequenced using 3’ Tag-Seq to an achieved average depth of 3.6 million reads/sample. Transcripts, mapped to ARS-UCD1.2, were quantified. Differential expression (DE) analyses were performed in DESeq2 with a significance threshold for false discovery rate of 0.05. In adipose, 4 loci (MISP3, APOL6, SLC25A4, S100A12) were DE due to ZH on d 3, and 2 (RRAD, ALB) were DE due to the interaction of HS and ZH on d 10 (Padj<0.05). In muscle, 40 loci (including TENM4 and OAZ1) were DE due to ZH on d 10 and 6 loci (HIF1A, LOC101903734, PDZD9, HNRNPU, MTUS1, TMCO6) were DE due to environment on d 21 (Padj<0.05). To explore biological pathways altered by environment, supplement, and their interaction, loci with DE (Praw<0.05) were evaluated in Ingenuity Pathway Analysis. In adipose, 509 pathways were predicted to be altered (P<0.01): 202 due to HS, 126 due to ZH, and 181 due to the interaction; these included inflammatory pathways predicted to be upregulated due to HS but downregulated due to the interaction of HS and ZH. In muscle, 113 pathways were predicted to be altered (P<0.01): 23 due to HS, 66 due to ZH, and 24 due to the interaction of HS and ZH. Loci and pathway data in muscle suggest HS induced oxidative stress and that the stress response was moderated by ZH. Metabolic pathways were predicted to be altered due to HS, ZH, and their interaction in both tissues. These data provide evidence that HS and ZH interact to alter expression of genes in metabolic and immune function pathways and that ZH moderates some adverse effects of HS.