Introduction: Osteoarthritis is a common joint disease, affecting many people worldwide, especially people over 65 years old. As effective medical treatment is lacking and the increased side effects of available drugs for osteoarthritis treatment, this study aimed to compare the outcome of Avosoy and Crocin extracts on pain intensity and radiographic changes in osteoarthritis patients. Materials and Methods: This clinical trial was performed on osteoarthritis patients aged 40–75 years with joint injury of grade 2–3 confirmed by radiographic images. Patients were randomly divided into two groups of 30 patients. One group was given avocado/soybean extract (Avosoy) with vitamin D (Vit D; 50,000-IU/week) and 500mg calcium (Ca) daily. Another group received Crocin with Vit D (50,000-IU/week) and 500mg Ca daily. After four months of drug use, the final questionnaire was filled in both groups. The data were analyzed in SPSS 22 software after collecting information. Results: No significant difference was found in the mean pain intensity before and after the intervention in the Avosoy group (P = 0.06), but a significant decrease was found in the pain intensity of patients in the Crocin group (P <0.001). Furthermore, no significant difference was found in the mean severity of osteoarthritis symptoms before and after intervention in the Avosoy group (P = 0.051), but a significant decrease in the severity of osteoarthritis symptoms and knee discomfort was found in the crocin group (P < 0.001). Our findings revealed a decrease in difficulties with activities of daily life, recreation, and exercise in both groups, but no radiological changes were observed. Conclusion: The present study demonstrated that treatment with Crocin has a better effect in decreasing the severity of pain, symptoms of osteoarthritis, and knee discomfort when compared with Avosoy, resulting in improvement of quality of life. Thus, its use could be recommended for patients suffering from osteoarthritis