Background Psoriasis is a complex disease associated with multiple comorbidities, including metabolic syndrome and leaky gut syndrome. Dietary lifestyle interventions have been reported to affect the disease in terms of lesional severity. It remains unclear how diets affect these comorbidities and the general health in psoriasis patients. Modified intermittent fasting (MIF) on 2 nonconsecutive days has shown beneficial effects on metabolic parameters. A significant advantage of MIF over the currently investigated dietary changes is its feasibility. Objective Here, we aim to study the effects of MIF on skin, gut, and metabolic health in psoriasis patients. Methods A 2-arm pilot randomized controlled open cross-over study will be performed in 24 patients with psoriasis. Patients will be randomized 1:1 to either start with 12 weeks of MIF and go on a subsequent regular diet for another 12 weeks or start with 12 weeks of regular diet and do subsequent MIF for 12 weeks. The following parameters will be assessed: demographics, disease phenotype, medical and familial history, psoriasis severity, dermatology-specific and general quality of life, nutritional and physical habits, mental and intestinal health, intestinal and cutaneous integrity, inflammatory and metabolic markers, and satisfaction. Results A total of 24 participants have been enrolled in the study. The final visit is foreseen for June 2021. Conclusions The aim is to uncover the effects of MIF on psoriasis severity and gut health integrity through clinical and molecular investigation. More precisely, we want to map the evolution of the different markers, such as psoriasis severity, permeability, and inflammation, in response to MIF as compared to a regular diet,. Understanding how dietary lifestyles can affect epithelial lineages, such as the skin and gut, will greatly improve our understanding of the development of psoriasis and may offer a nonpharmacological venue for treatments. Trial Registration ClinicalTrials.gov NCT04418791; https://clinicaltrials.gov/ct2/show/NCT04418791 International Registered Report Identifier (IRRID) DERR1-10.2196/26405