Background: Major depressive disorders (MDD) is common worldwide, and it causes significant functional impairment. Evidence-based therapies significantly address MDD symptoms severity; therefore, we aimed to investigate the effectiveness of pharmacotherapy (PTh), cognitive behaviour therapy (CBT), and Islam-based interventions (IBIs) to treat symptoms severity of patients MDD-m. Methods: This RCT was conducted by the Department of Applied Psychology, Government College University Faisalabad, from December 20, 2020, to October 31, 2021, at different hospitals in Faisalabad, Pakistan. Patients with MDD-m were allocated to three different evidence-based treatment approaches (i.e. PTh, CBT, & IBIs). Patients Health Questionnaire; Positive & Negative Affect Scale, Digit Span Scale, Standard Progressive Matrices, Self-Esteem Scale and Decision-Making Questionnaire were administered. SPSS version 27 was used to analyze the data. Results: A total of 210 were approached, 159 were assessed for eligibility, and 118 met the inclusion criteria, including males 66(55.94%) and females 52(44.06%) with the age range of 22 to 46 years. Findings reported all the treatment interventions produced significant treatment outcomes to reduce the depressive symptoms and improve memory, reasoning ability, decision-making skills, self-esteem, and wellbeing. PTh was an effective supportive intervention, while CBT and IBIs played an effective role as reeducative constructive therapies. Conclusion: All three interventions seem to be effective for major depressive disorder with mild severity, and CBT and IBIs emerged as more efficient and constructive therapies for MDD-m.