ImportanceThe youth mental health crisis is exacerbated for Latinx adolescents, a group whose families are targets of anti-immigrant rhetoric and policy.ObjectiveTo investigate how immigration-related stressors are associated with disruptions in parent-child relationships and, in turn, the mental health symptoms of Latinx adolescents.Design, Setting, and ParticipantsData for this prospective cohort study of adolescent-mother dyads were derived from surveys completed at 3 time points spanning 4 years (time 1 [T1] in 2018, time 2 [T2] in 2020, and time 3 [T3] in 2022). Mediation analyses estimated paths from immigration-related stressors to parent-child relationship qualities to mental health symptoms from early to late adolescence. Multivariable and multivariate linear models within a structural equation modeling framework regressed mediators and outcome variables on their own T1 values, offering a scientifically rigorous test of mediation. The setting was a school district in suburban Atlanta, Georgia, and included Latinx adolescents (ages 11-16 years) randomly selected from grade and gender strata. Data were analyzed from June 2023 to March 2024.ExposuresThe primary independent variables were T1 mother reports of anti-immigrant worry and behavioral modification and adolescent reports of family member detention or deportation. Mediating variables were the reports of parental support and parent-child conflict of T2 adolescents.Main Outcomes and MeasuresT3 adolescent reports of past 6-month internalizing and externalizing symptoms.ResultsA total of 547 Latinx adolescents (mean [SD] age, 13.3 [1.0] years; 303 female [55.4%]; 244 male [44.6%]) were included in this study. Response rates were 65.2% (547 of 839) among contacted parents and 95.3% (547 of 574) among contacted adolescents with parental permission. Four-year retention rates were 67% (366 of 547 adolescents) and 65% (177 of 271 mothers). Structural model results showed that T1 anti-immigrant worry and behavioral modification was associated with T3 increases in externalizing symptoms indirectly through T1 to T2 increases in parent-child conflict (β = 0.03; SE = 0.02; 95% CI, 0-0.08). For girls, T1 family member deportation or detention was associated with T1 to T3 increases in internalizing and externalizing symptoms indirectly through T1 to T2 declines in parental support (internalizing: β = 0.04; SE = 0.02; 95% CI, 0-0.08; externalizing: β = 0.03; SE = 0.02; 95% CI, 0-0.07). Sensitivity analyses supported structural model findings.Conclusion and RelevanceResults of this cohort study suggest that legislative bodies, the health care system, and educational institutions should implement safeguards to mitigate potential harm conferred by anti-immigrant environments for parent-child relationships and, in turn, Latinx adolescents’ mental health.