Background: The treatment of moderate-to-severe psoriasis has advanced significantly with the use of biologic treatments. Objective: To compare the effectiveness, safety, and impact on quality of life of biologic therapies versus conventional systemic therapies for moderate-to-severe psoriasis, using evidence from 2015 to 2025, focusing on the implications for understudied regions such as Iraq and the Middle East. Methods: Data was collected using "Embase," "MEDLINE," "PubMed," and "Cochrane Central Register." The study includes 45 randomized controlled trials. Additionally, 25 key real-world evidence studies were included for qualitative synthesis to provide context on long-term drug survival, quality of life, and regional applicability. Efficacy was assessed using Psoriasis Area Severity Index (PASI) 75, 90, and 100 response rates at both short-term (10-16 weeks) and long-term (44-60 weeks) intervals. Statistical analyses included Bayesian network meta-analysis and hierarchical cluster analysis. Results: Biological therapies, specifically IL-17 and IL-23 inhibitors, outperformed conventional therapy. In real-world research, 59.7% of patients on secukinumab attained PASI 90 at 3 months, compared to 18.8% with traditional systemics (p<0.001). Biologics also demonstrated a faster time to response (3.04 vs. 6.12 days), increased treatment survival rates, and better quality of life. Safety profiles were favorable, with class-specific hazards (e.g., infections, candidiasis) managed by screening. Conclusions: Biological treatments represent an improved therapy approach for moderate-to-severe psoriasis, providing more rapid, effective, and long-term clearance with a manageable safety profile. These findings call for revisiting traditional first-line therapy strategies, particularly in countries like those in the Middle East, where local data is lacking.