Background: Cannabis is the most commonly used illicit substance worldwide. In Chile, the prevalence of cannabis use among adolescents is the highest in the Americas. Our aim was to identify prevalence trends of cannabis use and associated factors in adolescents. Methods: We performed multivariate logistic regression analyses of 416,417 cross-sectional school-based surveys of adolescents from 8th to 12th grade conducted between 2003 and 2017 in Chile. Cannabis use was the dependent variable. Age, gender, socio-economic variables, and factors on the individual, school and family level were assessed as independent variables. Results: The prevalence of cannabis use in the past year increased from 13.6% in 2003 to 31.3% in 2017 in a linear trend (F(df:1,6) = 27.6; R2 = 0.79; p < 0.01). The strongest association with cannabis use was seen for having friends who regularly use cannabis, and low perceived risk of cannabis use. Between 2003 and 2017, the strength of association between the variable having friends who regularly use cannabis and cannabis use decreased from OR = 6.2 to OR = 2.9, in a significant linear trend (F(df:1,6) = 60.5; R2 = 0.89; p < 0.01); whereas the OR for low parental rejection of cannabis use with cannabis use increased in a linear trend (F(df:1,6) = 22.8; R2 = 0.75, p < 0.01) from OR = 1.2 to OR = 2.1. Conclusions: Increasing cannabis use of adolescents in Chile requires adjustments of prevention strategies. Prevalence factors identified here constitute potential targets for interventions.