Cannabis use during adolescence and young adulthood may affect academic achievement; however, the magnitude of association remains unclear. To conduct a systematic review evaluating the association between cannabis use and academic performance. CINAHL, EMBASE, MEDLINE, PsycInfo, PubMed, Scopus, and Web of Science from inception to November 10, 2023. Observational studies examining the association of cannabis use with academic outcomes were selected. The literature search identified 17 622 unique citations. Pairs of reviewers independently assessed risk of bias and extracted data. Both random-effects models and fixed-effects models were used for meta-analyses, and the Grading of Recommendations Assessment, Development, and Evaluation approach was applied to evaluate the certainty of evidence for each outcome. Data were analyzed from April 6 to May 25, 2024. School grades, school dropout, school absenteeism, grade retention, high school completion, university enrollment, postsecondary degree attainment, and unemployment. Sixty-three studies including 438 329 individuals proved eligible for analysis. Moderate-certainty evidence showed cannabis use during adolescence and young adulthood was probably associated with lower school grades (odds ratio [OR], 0.61 [95% CI, 0.52-0.71] for grade B and above); less likelihood of high school completion (OR, 0.50 [95% CI, 0.33-0.76]), university enrollment (OR, 0.72 [95% CI, 0.60-0.87]), and postsecondary degree attainment (OR, 0.69 [95% CI, 0.62-0.77]); and increased school dropout rate (OR, 2.19 [95% CI, 1.73-2.78]) and school absenteeism (OR, 2.31 [95% CI, 1.76-3.03]). Absolute risk effects ranged from 7% to 14%. Low-certainty evidence suggested that cannabis use may be associated with increased unemployment (OR, 1.50 [95% CI, 1.15-1.96]), with an absolute risk increase of 9%. Subgroup analyses with moderate credibility showed worse academic outcomes for frequent cannabis users and for students who began cannabis use earlier. Cannabis use during adolescence and young adulthood was probably associated with increases in school absenteeism and dropout; reduced likelihood of obtaining high academic grades, graduating high school, enrolling in university, and postsecondary degree attainment; and perhaps increased unemployment. Further research is needed to identify interventions and policies that mitigate upstream and downstream factors associated with early cannabis exposure.