In recent years, colchicine has been used to reduce the risk of cardiovascular events; in particular, it has been effectively used for the treatment of atrial fibrillation (AF). We first discovered that colchicine can treat AF in a rat model and that it can reverse the effects of atrial fibrosis. To illustrate the potential therapeutic mechanism of colchicine against AF, we performed comparative transcriptome analyses; our aim was to elucidate the therapeutic effects of colchicine so as to improve treatment and prognoses of AF. Genomics and bioinformatics analyses revealed that the IL-17 signaling pathway, and renin secretion pathway are involved in the mechanism of action of colchicine. Furthermore, there was a significant correlation between overlapping genes in the two groups of differentially expressed genes. The genes encoding Akap4, Pcdha9, Gp2, Cd177, Krt15, Aqp3, Chia, and Bpifb1 were pivotal and possible action sites for the therapeutic mechanisms of colchicine. We conclude that AF involves a multifactorial pathological process. The mechanisms underlying the action of colchicine in the treatment of AF warrant further studies.