Preliminary clinical data suggest that pain reduction through fasting may be effective for different diagnoses. This uncontrolled observational clinical study examined the effects of prolonged modified fasting on pain and functional parameters in hip and knee osteoarthritis. Patients admitted to the inpatient department of Internal Medicine and Nature-based Therapies of the Immanuel Hospital Berlin between February 2018 and December 2020 answered questionnaires at the beginning and end of inpatient treatment, as well as at 3, 6, and 12 months after discharge. Additionally, selected blood and anthropometric parameters, as well as subjective pain ratings, were routinely assessed during the inpatient stay. Fasting was the only common intervention for all patients, being performed as part of a multimodal integrative treatment program, with a daily caloric intake of <600 kcal for 7.7 ± 1.7 days. N = 125 consecutive patients were included. The results revealed an amelioration of overall symptomatology (WOMAC Index score: −14.8 ± 13.31;p< 0.001; d = 0.78) and pain alleviation (NRS Pain: −2.7 ± 1.98,p< 0.001, d = 1.48). Pain medication was reduced, stopped, or replaced by herbal remedies in 36% of patients. Improvements were also observed in secondary outcome parameters, including increased quality of life (WHO-5: +4.5 ± 4.94,p< 0.001, d = 0.94), reduced anxiety (HADS-A: −2.1 ± 2.91,p< 0001, d = 0.55) and depression (HADS-D: −2.3 ± 3.01,p< 0.001, d = 0.65), and decreases in body weight (−3.6 kg ± 1.65,p< 0.001, d = 0.21) and blood pressure (systolic: −6.2 ± 15.93,p< 0.001, d = 0.43; diastolic: −3.7 ± 10.55,p< 0.001, d = 0.43). The results suggest that patients with osteoarthritis of the lower extremities may benefit from prolonged fasting as part of a multimodal integrative treatment to improve quality of life, pain, and disease-specific functional parameters. Confirmatory randomized controlled trials are warranted to further investigate these hypotheses.