Background Non-compliance with inhaled corticosteroids in pediatric asthmatics is common and can lead to worsening airways and even systemic inflammation. Therefore, complementary strategies alongside pharmacological treatment, such as certain nutrients and dietary patterns, may offer easy and acceptable approaches to mitigate inflammation and alleviate asthma manifestations. The current work aimed to explore the protective effects of omega-3 polyunsaturated fatty acid supplements in asthmatic children and adolescents. Methods The current longitudinal, prospective, double-blind, controlled study included 116 children and adolescents with asthma, ranging in age from 6 to 17.6 years, randomly assigned into two age- and sex-matched groups. Over 6 months, in addition to their regular controller medications, 56 participants received 1200 mg of omega-3 supplement, while 60 received a placebo. The participants were evaluated at the beginning of the study, after 6 months of supplementation, and 6 months after discontinuation, using asthma severity grading, a childhood asthma control test (C-ACT), and pulmonary function tests (PFTs), in addition to measurements of antioxidant and inflammatory markers (glutathione reductase [GR], malondialdehyde [MDA], matrix metalloproteinase-9 [MMP-9], and interleukin-17 [IL-17]). Results In the omega-3 group, asthma severity grades, C-ACT scores, PFTs, and serum levels of GR, MDA, MMP-9, and IL-17 significantly improved after 6 months of supplementation in comparison to the placebo group (p < 0.001 vs. baseline; p < 0.001 vs. placebo). Specifically, moderate and severe asthma cases declined from 76.7 to 26.7%, while not well-controlled and very poorly controlled asthma decreased from 100 to 17.8%. Improvements were significantly maintained, albeit to a lesser extent, for 6 months after discontinuation, with moderate and severe asthma cases remaining at 37.5% and not well-controlled and very poorly controlled asthma at 33.9% (p < 0.001 vs. baseline; p < 0.001 vs. placebo). Adverse effects were reported in 32.1% of the omega-3 group, primarily fishy burping (26.8%) and mild gastrointestinal symptoms (5.4%). Conclusion Omega-3 supplementation may serve as a promising adjunct therapy in asthma management, potentially reducing severity, enhancing control, improving lung function, and lowering inflammatory markers in pediatric asthma patients.