Background Prevention of depression and anxiety disorders early in life is a global health priority. Evidence on risk and protective factors for youth internalizing disorders indicates that the family represents a strategic setting to target preventive efforts. Despite this evidence base, there is a lack of accessible, cost-effective preventive programs for parents of adolescents. To address this gap, we recently developed the Partners in Parenting (PiP) program—an individually tailored Web-based parenting program targeting evidence-based parenting risk and protective factors for adolescent depression and anxiety disorders. We previously reported the postintervention outcomes of a single-blinded parallel-group superiority randomized controlled trial (RCT) in which PiP was found to significantly improve self-reported parenting compared with an active-control condition (educational factsheets). Objective This study aimed to evaluate the effects of the PiP program on parenting risk and protective factors and symptoms of adolescent depression and anxiety using data from the final assessment time point (12-month follow-up) of this RCT. Methods Parents (n=359) and adolescents (n=332) were recruited primarily from secondary schools and completed Web-based assessments of parenting and adolescent depression and anxiety symptoms at baseline, postintervention (3 months later), and 12-month follow-up (317 parents, 287 adolescents). Parents in the PiP intervention condition received personalized feedback about their parenting and were recommended a series of up to 9 interactive modules. Control group parents received access to 5 educational factsheets about adolescent development and mental health. Both groups received a weekly 5-min phone call to encourage progress through their program. Results Intervention group parents completed an average of 73.7% of their intended program. For the primary outcome of parent-reported parenting, the intervention group showed significantly greater improvement from baseline to 12-month follow-up compared with controls, with a medium effect size (Cohen d=0.51; 95% CI 0.30 to 0.72). When transformed data were used, greater reduction in parent-reported adolescent depressive symptoms was observed in the intervention group (Cohen d=−0.21; 95% CI −0.42 to −0.01). Mediation analyses revealed that these effects were mediated by improvements in parenting (indirect effect b=−0.08; 95% CI −0.16 to −0.01). No other significant intervention effects were found for adolescent-reported parenting or adolescent depression or anxiety symptoms. Both groups showed significant reductions in anxiety (both reporters) and depressive (parent reported) symptoms. Conclusions PiP improved self-reported parenting for up to 9 months postintervention, but its effects on adolescent symptoms were less conclusive, and parent-reported changes were not perceived by adolescents. Nonetheless, given its scalability, PiP may be a useful low-cost, sustainable program to empower parents of adolescents. Trial Registration Australian Clinical Trials Registration Number (ACTRN): 12615000328572; http://www.anzctr.org.au/ACTRN12615000328572.aspx (Archived by WebCite at http://www.webcitation.org/6qgsZ3Aqj).