Background: Psoriasis is a noninfectious chronic disease with unknown etiology, but multiple triggers and much comorbidity, characterized by well-defined dry scaly erythematous patches covered with adherent silvery white scales predominantly on the extensor surfaces. The risks and adverse effects of long-term contemporary therapy outweigh the benefits. Ayurveda approaches psoriasis as Vata-Kaphaja Kushtha and individualized approach to patient is advised. This study was done to assay the efficacy and safety of comprehensive Ayurvedic therapy, involving Panchakarma, Takradhara, and Rasayana in the management of plaque psoriasis. Objectives: To evaluate clinical efficacy and safety of comprehensive Ayurvedic therapy in psoriasis. Materials and methods: A prospective, open-label multicenter study was carried out at two peripheral centers of Central Council for Research in Ayurvedic Sciences (CCRAS). A total of 85 patients diagnosed with plaque psoriasis were recruited and administered Vamana Karma followed by Takradhara and Rasayana therapy. The total duration of therapy was 66 days. Assessment was done based on the relief in clinical symptoms of psoriasis, psoriasis area and severity index (PASI) score, and dermatology life quality index (DLQI). Safety assessment was done through analysis of liver function tests (LFTs) and kidney function tests (KFTs) before and after the trial period. Results: The treatment protocol provided statistically significant relief in symptoms of psoriasis, PASI, and DLQI. The PASI score improved from 23.594 at baseline to 5.199 at the end of trial with p value < 0.001. There was significant improvement in all parameters of DLQI at the end of 66th day and no adverse events (AEs) were noted during the trial period. The values of LFT and KFT were observed to be within limits during the entire period. Conclusion: Treatment protocol involving Panchakarma, Takradhara, and Rasayana was effective in producing relief in plaque psoriasis.