Oral vitamin K antagonists (VKAs), warfarin, have been in routine clinical use for almost 70 years for various cardiovascular conditions. Direct-Acting Oral Anticoagulants (DOACs) have emerged as competitive alternatives for VKAs to prevent stroke in patients with non-valvular atrial fibrillation (AF) and have become the preferred choice in several clinical indications for anticoagulation. Recent guidelines have limited the use of DOACs to patients with non-valvular AF to reduce the risk of cardioembolic complications and to treat venous thromboembolism (VTE). Although emerging evidence is suggestive of its high efficacy, there was a lack of data to support DOACs safety profile in patients with mechanical valve prosthesis, intracardiac thrombi, or other conditions such as cardiac device implantation or catheter ablation. Therefore, several clinical trials have been conducted to assess the beneficial effects of using DOACs, instead of VKAs, for various non-guideline-approved indications. This review aimed to discuss the current guideline-approved indications for DOACs, advantages, and limitations of DOACs use in various clinical indications highlighting the potential emerging indications and remaining challenges for DOACs use. Several considerations are in favour of switching from warfarin to DOACs including superior efficacy, better adverse effect profile, fewer drug-drug interactions, and they do not require frequent international normalized ratio (INR) monitoring. Large randomized controlled trials are required to determine the safety and efficacy of their use in various clinical indications.