Objective The purpose of this study was to investigate the effects of xanthine oxidase (XO) inhibitors (allopurinol and febuxostat) on atrial electrical remodeling in a rabbit model of atrial fibrillation (AF) induced by rapid atrial pacing (RAP). Methods Twenty-four healthy male New Zealand white rabbits were randomly divided into four groups:sham-operated group (S group), RAP group (P group), RAP-allopurinol group (ALL group), and RAP-febuxostat group (FP group). Enzyme-linked immunosorbent assay (ELISA) kit was used to detect the activity of high-sensitivity C-reactive protein (hs-CRP), growth differentiation factor-15 (GDF-15) and galectin-3, and the activity of superoxide dismutase (SOD) and the levels of XO and xanthine dehydrogenase (XDH) in left atrial tissues. Before pacing and four weeks after RAP, electrophysiological examinations were performed to evaluate the atrial effective refractory period at 200 ms (AERP200) and the inducibility of AF. Real-time fluorescence quantitative polymerase chain reaction (PCR) and Western blotting were used to detect the messenger RNA (mRNA) and protein expressions of calcium voltage-gated channel subunit α1C (Cav1.2) and potassium voltage-gated channel subfamily D3 (Kv4.3). SPSS statistics 26.0 was used for data analysis. According to different data type, one-way analysis of variance or χ²test was used for data comparison between groups. Results Compared with S group, the SOD activity was significantly decreased, and the levels of XO, XDH, hs-CRP, GDF-15 and galectin-3 were increased in P group, and the differences were statistically significant (P<0.01). After using XO inhibitor, the activity of SOD recovered significantly, and the activities of XO, hs-CRP, GDF-15 and galectin-3 were significantly decreased, and the differences were statistically significant (P<0.05). The activity of SOD in FP group was significantly higher than in ALL group, whereas the activities of XDH, hs-CRP, GDF-15 and galectin-3 in FP group were obviously lower compared with ALL group (P<0.05). However, there was no significant difference in the level of XO between FP group and ALL group (P>0.05). Additionally, the activity of XDH in FP group was significantly lower than in P group, and the differences were statistically significant (P<0.01). Nevertheless, there was no significant diffe-rence in the level of XDH between ALL group and P group (P>0.05). After RAP, AERP200 was significantly lower in P group than S group (P<0.01), and the AERP200 of FP group was significantly higher than that of P group and ALL group (P<0.05). Except for S group, AF inducibility of P group, ALL group and FP group was significantly higher than the baseline before pacing (P<0.05). After the intervention of XO inhibitors, the AF inducibility was reduced to a certain extent, especially in FP group. RAP could reduce down-regulation of Cav1.2 and Kv4.3 mRNA and protein expression levels in left atrial tissue, and the intervention of XO inhibitors could partially inhibit these changes, which was particularly evident in FP group. Conclusion XO inhibitors (especially febuxostat) could inhibit the down-regulation of Cav1.2 and Kv4.3 expression levels in left atrial by reducing inflammation and oxidative stress damage, thereby prolonging AERP, reducing the inducibility of AF, and mitigating atrial electrical remodeling.