Background and objective: To evaluate the effectiveness of weekly Methotrexate versus everyday Apremilast in treating patients with moderate to advanced plaque psoriasis who visit the hospital dermatology OPD. Methods: In a comparative analysis, the study included 50 people with moderate-to-severe plaque psoriasis. The diagnosis of psoriasis was made using clinical data. The psoriasis area and severity index (PASI) was used to evaluate the severity of the condition. Two groups of patients were formed; group A (25 patients) received methotrexate, while group B (25 patients) received apremilast. At the 0, 1, 2, and 4th treatment months, patients were evaluated using the Psoriasis Area and Severity Index (PASI) scores. The effectiveness of the medications was compared using PASI. Results: 22 (61%), 11 (30.56%), 9 (25%), and 3 (8.34%) individuals had nail involvement. Group B patients with baseline PASI scores >25 experienced a substantial drop in PASI score after one month, compared to group A patients who did not. 9 of 13 patients had lower scores after 2 months. Three of four patients had lower PASI scores after three months. One patient never replied.