Background: Personality is associated with health behaviors, such as smoking and substance abuse, yet there is little information about the relationship between optimism and tobacco smoking or substance abuse among high school students. Objectives: The aim of the present study was to determine the association between optimism or pessimism in predicting tobacco smoking and substance abuse among high school students in southeast of Iran. Methods: In this study, 1094 students of high schools in Zahedan city, southeast of Iran, were selected using proportionally multistage sampling. Cigarette and hookah smoking status, substance abuse, optimism, and other potential confounders were measured using a self-administered questionnaire. The data were analyzed using chi-square, analysis of variance (ANOVA) tests and ordinal logistic regression in Stata.14 software. Results: According to the results of present study, the prevalence of cigarette smoking and ever hookah smoking was 32.7% and 36.1%, respectively. About 11.2% of students had used at least one illicit drug. After controlling potential confounders, optimism score was negatively related to cigarette smoking stages (OR = 0.90, 95% CI: 0.79 to 0.97) and illicit drugs use (OR = 0.91, 95% CI: 0.70 to 0.96) yet was not associated with hookah smoking (OR = 0.98, 95% CI: 0.82 to 1.31). Conclusions: Optimism and pessimism have an important role in tendency of students to tobacco smoking and substance abuse. On the other hand, the co-occurrence of smoking and substance abuse is high among students with low optimism scores. Therefore, educating and consulting students regarding positivism and promising could prevent from smoking and substance abuse and probably transition to higher stages.