Background: Chronic diseases have a substantial impact on global health. Plant-based diets, which are abundant in fiber and antioxidants, consistently demonstrate advantages in mitigating cardiovascular risks, controlling diabetes, decreasing cancer rates, and facilitating healthy weight maintenance. Methods: This study evaluated the feasibility, acceptability, and initial efficacy of a 21-day virtual whole-food plant-based (WFPB) dietary intervention, implemented by the non-profit organization Plant Powered Metro New York, among 139 participants. The intervention consisted of weekly educational and mentorship sessions. A mixed-methods study design was used to evaluate the program. Feasibility was assessed based on program attendance. Acceptability was assessed based on self-reported program satisfaction on survey and key informant focus group responses. Pre- and post-program surveys measured changes in perceptions and knowledge of WFPB nutrition, self-efficacy in cooking, adherence to the diet, health-related quality-of-life metrics, and mental health (Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7). Changes in anthropometric measures, including BMI, waist circumference, HbA1c, LDL, total cholesterol, and blood pressure, were measured in a subsample of participants. Pre- to post-program changes were assessed using Wilcoxon signed- rank, McNemar, or McNemar-Bowkers tests. Inductive content analysis was used to assess qualitative data obtained from the focus group participants. Results: Participants attended an average of 73% of the educational sessions, and 89.9% of participants found the program to be satisfactory, describing the experience as “Excellent” or “Good.” Statistically significant improvements were found in self-reported WFPB nutrition knowledge and perceptions regarding challenge, cost, and the ability to adopt and cook a WFPB diet. Participants from the focus group identified program benefits, such as education and improved health, and challenges, such as scheduling issues and misconceptions about WFPB diets. Recommendations include addressing cost misconceptions and providing culturally relevant recipes to enhance program acceptance. There were also statistically significant self- reported improvements in health-related QoL metrics, including pain (other than headaches), headaches, mobility, breathing, skin, gastrointestinal symptoms, hormonal symptoms, sleep, energy, moodiness, mental clarity, and cravings for unhealthy food. There were median decreases of 2.85 points on the PHQ-9 and 1.82 points on the GAD-7, 1.16 kg/m2 in BMI, and 1.65 inches in waist circumference (all p=<0.0001). No significant changes were observed in HbA1c, LDL cholesterol, total cholesterol, or blood pressure levels. Conclusion: The 21-day program was associated with improvements in participants' perceptions of knowledge and self-efficacy regarding WFPB nutrition, self-reported quality-of-life, mental health, and anthropometric measures, including BMI and waist circumference. Future research is needed to assess the long-term results of the program, and to assess the program in patient populations with specific chronic diseases.