Background: Psoriasis is a chronic inflammatory systemic condition depicting a high relapse rate. The mainstream drugs for treating psoriasis in current times are phosphodiesterase type 4 inhibitor and- Apremilast and a dihydrofolate reductase inhibitor namely methotrexate. Aim: The present study was done to comparatively assess the efficacy of methotrexate with apremilast to methotrexate alone in moderate to severe cases of chronic plaque psoriasis. Methods: The present prospective comparative evaluation included 80 adult subjects with confirmed diagnosis of chronic plaque psoriasis. A comprehensive clinical and demographic evaluation was done in all subjects with performed structured proforma. Total study subjects were divided into 2 groups of 40 subjects each where Group I subjects were treated using combined oral methotrexate and Apremilast and Group II using Oral Apremilast only and were assessed at 4 and 12 weeks after investigations when required. Results: In the present study, 55% (n=44) of subjects were from the age range of 31-50 years and comorbidities including hypertension, diabetes, and others were reported in 27.5% (n=22) subjects. The PASI scores from Group I were lower compared to Group II at all first, second, and third follow-ups. A significantly higher reduction in mean PASI scores was seen in Group I at the follow-ups with 89% improvement at 12 weeks follow-up. Conclusions: The present study concludes that multidrug therapy with combined Apremilast and Methotrexate has better efficacy in treating chronic plaque psoriasis in comparison to methotrexate alone.