Apixaban plays a crucial role in preventing cardioembolic events in patients with nonvalvular atrial fibrillation (NVAF). However, in clinical practice, physicians often adjust apixaban dosing based on kidney function, deviating from guideline-recommended dosing. This study investigated the effects of real-world, off-label apixaban dosing on long-term outcomes in patients with heart failure (HF), NVAF, and end-stage kidney disease (ESKD). We analyzed data from a HF registry of patients with NVAF and ESKD between 2018 and 2024. The inclusion criteria comprised all patients treated with apixaban. Patients were categorized according to the strength of the apixaban dose administered. Outcomes, including bleeding events, systemic thromboembolic events, and all-cause mortality, were compared. Among 480 patients, 265 (55.2%), with a mean age of 77.3 ± 10.1 years, received an off-label underdose of apixaban. Baseline characteristics, including CHA2DS2-VASc and HAS-BLED scores, were similar across groups. Over a median follow-up of 48 months, no significant differences in systemic thromboembolic events or mortality were observed between the off-label underdose group and those receiving standard doses or off-label overdoses (P = .705). Similarly, no significant differences were observed in bleeding risk (underdose vs standard, P = .600; overdose vs standard, P = .395; underdose vs overdose, P = .469). In multivariate analysis, the CHA2DS2-VASc score was an independent predictor of thromboembolic events (odds ratio 1.818, 95% confidence interval 1.081-3.058; P = .024). In patients with HF, NVAF, and ESKD, off-label apixaban dosing was not associated with an increased risk of systemic thromboembolic events, mortality, or bleeding, highlighting the potential for personalized apixaban dosing based on patient-specific factors and pharmacokinetics, particularly in Asian populations.