Low energy and fatigue are key symptoms of Major Depressive Disorder (MDD) and even when depression is partially treated, fatigue often remains as a persistent residual symptom. MDD was the third leading cause of global disease burden in 2008 and is projected by World Health Organization (WHO) to rank first by 2030. Globally, 15.1% of adults and 6.0% of minor’s experience fatigue, while 10.1% of adults and 1.5% of minors suffer from chronic fatigue. Hence, it is essential to investigate further strategies to enhance human energy and alleviate fatigue. Traditional natural remedies are gaining attention as alternative therapies for various diseases worldwide. For centuries, various natural substances have been used to enhance physical and mental energy, combating fatigue, playing a vital role in mental health support, particularly in managing conditions like depression. This review aims to fill the gap in comprehensive literature reviews regarding those natural substances in Southeast Asian countries. It focuses on potential natural substances from six countries: Vietnam, Indonesia, Philippines, Bhutan, Malaysia and Thailand. By summarizing and comparing these substances, we can identify shared effects and properties, as well as unique characteristics that differentiate them across various regions. This review examines 454 natural substances from six countries, used to enhance energy and combat fatigue, with a focus on plant-based sources, excluding animals and insects. Among those natural substances, 6.2% are from the Fabaceae family, followed by 4.8% from the Rubiaceae family and 4.2% from the Zingiberaceae family. In all a the natural substances used, leaves represent the largest portion at 22.1%, followed by roots at 15.9% and fruits at 13.9%. This review is an attempt to study and compile the traditional and scientific aspects of the potential energizing substances used in Southeast Asia reported till date.