Background: Good mental health improves the overall quality of life. Anxiety and depression in post-treatment cancer survivors is common and can affect adversely on the individual. CanCovDirect is a novel, tele-medicine self-care intervention for cancer survivors. We practiced a randomized controlled superiority trial to compare CanCovDirect with usual standard care (SC) in this population.Methods: Individuals completing cancer treatment within the past 3 years who had symptoms with or without anxiety or depression were recruited from clinical and community settings in Northern Kerala. We allocated the participants using block randomization (CanCovDirect plus SC or to SC alone). Assessments of anxiety and depression severity (Centre for Epidemiological Studies-Depression scale [CES-D]; primary outcome) and secondary outcomes anxiety symptoms (Hospital Anxiety and Depression Scale) health-related quality of life (Short Form Survey-12 mental and physical component summaries), were conducted at baseline, as well as 3 and 6 months (primary time point). Analyses of outcomes were adjusted for covariates using linear regression. Results: Participants recruited between June 2020 and November 2020 were randomly assigned to CanCovDirect (n = 152) or SC (n = 152). Among 350 participants randomly assigned, 304 (86.85%) completed the primary outcome at 6 months. CanCovDirect participants reported less severe anxiety and depressive symptoms on the CES-D than SC participants at 6 months, adjusted effect size (ES) 1.68 (95% CI, 1.28 to 2.05). CanCovDirect participants also had significantly greater quality of life compared with SC. Exploratory analysis suggested that types of cancer was a modifier of the primary outcome (interaction term P value =.04); the intervention was effective in women (ES, 0.62; 95% CI, −0.45 to 0.89). Conclusions: CanCovDirect is an essential method of managing mild-moderate depression and anxiety symptoms in cancer survivors.