Background: Type 2 diabetes mellitus (T2DM) is common with obesity. Metformin is a first-line therapy for this condition. However, it has only a minor impact on weight loss in some patients.Aim: This study aimed to evaluate the effectiveness, tolerability, and safety of combining montelukast therapy with metformin in obese diabetic patients.Methods: One hundred obese diabetic adult patients were recruited and randomized into two equal groups. Group 1 received placebo plus metformin 2 g/d, and Group 2 received 2 g/d metformin plus 10 mg/d montelukast. Demographic, anthropometric measurements (e.g., body weight, body mass index [BMI], and visceral adiposity index), lipid profile, diabetes control measures (fasting blood glucose, glycated hemoglobin [HbA1c], and homeostatic model assessment for insulin resistance [HOMA-IR]), adiponectin, and inflammatory markers (e.g., TNF-α, IL-6, and leukotriene B4) were assessed and reported for each group at baseline and after 12 weeks of treatment.Results: Both interventions significantly reduced all the measured parameters, except for adiponectin and HDL-C, levels of which increased compared to baseline data (p < 0.001). The montelukast group significantly improved in all parameters compared to the placebo group (ANCOVA test p < 0.001). The percentage changes in BMI, HbA1c, HOMA-IR, and inflammatory markers were 5%, 9%, 41%, and 5%–30%, respectively, in the placebo group compared to 8%, 16%, 58%, and 50%–70%, respectively, in the montelukast group.Conclusion: Montelukast adjuvant therapy was superior to metformin-only therapy in diabetes control and weight loss, most likely due to its increased insulin sensitivity and anti-inflammatory properties. The combination was tolerable and safe throughout the study duration.Clinical Trial Registration: [Clinicaltrial.gov], identifier [NCT04075110].