Abstract Background Methamphetamine use not only impacts health and the economy but also causes social impairment, particularly among the poorly educated and underprivileged young populations among the hill tribes in northern Thailand. Youths are the most vulnerable population for methamphetamine use due to various factors, including parenting styles, childhood exposure, and location of the village. This qualitative approach aimed to investigate the perceived factors influencing the initiation of methamphetamine use among the Akha and Lahu youths in northern Thailand. Methods A qualitative approach was used to elicit the information from key informants of Akha and Lahu youths who lived in villages in Chiang Rai province. A sixteen-question guideline was developed and examined for quality by three experts in the field and piloted before use. In-depth interviews were conducted among 19 Akha and 22 Lahu youths, serving as key informants from four villages, in a private and confidential room in their villages between June and August 2018. Each interview lasted approximately an hour. A thematic analysis was performed to evaluate the information. Results In total, 41 participants (19 Akha and 22 Lahu) from 4 villages participated in the study. According to the context and content obtained, four major perceived factors (low self-esteem, family member use, positive expectation regarding methamphetamine use, and availability), and five supportive factors (social norm perception, school dropout, family level problems, poor economic, and no Thai citizenship) were found to contribute to the initiation of methamphetamine use among the Akha and Lahu youths in northern Thailand. Conclusions Akha and Lahu youths are initiating methamphetamine use due to several factors, including living in a poor family and in a remote area. All relevant government agencies with a mission to prevent and protect against methamphetamine use should consider the perceived factors influencing the initiation of methamphetamine use in these populations in order to develop a powerful program to stop methamphetamine use.