INTRODUCTION: Potent stimulants, such as methamphetamine, exert powerful psychological and physiological effects that could affect suicide risks. Therefore, the aim of this study was to investigate whether methamphetamine use is independently associated with suicidality after adjusting for potential confounding variables. METHODS: This case-control study investigated the independent role of methamphetamine use in suicidal ideation, suicide planning, and suicide attempts in 800 patients who were substance users receiving treatment from mental health hospitals in Saudi Arabia. Methamphetamine users and non-users comprised the case and control groups, respectively. Urine analyses were performed to verify the participants' self-reported drug use, and the Columbia-Suicide Severity Rating Scale, Addiction Severity Index, and Timeline Follow-Back approach were used in the data-gathering process. Multivariate analyses, adjusted for confounding factors, were conducted to assess the relationship between methamphetamine use and suicidality. Kaplan-Meier survival analysis was used to determine the survival probabilities of methamphetamine users and non-users. RESULTS: The proportion of methamphetamine users with a history of suicidality was significantly higher than that of non-users (30% vs. 20%, respectively; < 0.001), and a higher proportion of users attempted suicide (18% vs. 7%). The dose-response relationship revealed adjusted odds ratios increasing from 1.8 (95% confidence interval (CI): 1.3-2.5) in light users (1-2 times monthly) to 3.2 (95% CI: 2.3-4.4) in heavy users (every day), demonstrating that daily methamphetamine use significantly increased suicide risk. Compared with that of non-users, methamphetamine users had a significantly poorer survival rate (hazard ratio = 2.4, < 0.001). Hanging was the most common method of suicide, followed by self-poisoning. CONCLUSION: Methamphetamine use was identified as a strong independent predictor of suicidality. These findings underscore the critical need for comprehensive evaluations in mental health care, as well as tailored interventions and long-term monitoring of users to reduce the suicide risk in this vulnerable population.