Meeting food and nutritional security needs for a growing population is a global sustainability challenge due to the heavy reliance on a few cultivated crops for dietary requirements across the world. To ensure local food security, it is imperative to diversify dietary options with locally available, neglected, and underutilized crops (NUCs) with nutritional and biocultural significance. In this context, the present study aims to explore the role of NUCs for nutritional, ethnomedicinal, and agricultural relevance in two districts of eastern Uttar Pradesh, i.e., Mirzapur and Sonebhadra. Extensive field surveys were conducted in the study sites, and a total of 445 local respondents were interviewed based on structured questionnaires for calculating ethnobotanical indices, i.e., relative frequency of citation (RFC), frequency of citation (FC), use report (UR), and cultural importance index (CI) of NUCs. The study identified 116 NUCs belonging to 55 families and 103 genera. All reported NUCs had medicinal value; 55 were edible and used as food; and 41 had agricultural significance. Leaves were the most commonly used plant parts for medicinal purposes, followed by roots and stems, whereas flowers were the least commonly used parts. NUCs were used by the locals for their medicinal properties to treat various ailments, such as skin and eye problems, headaches, and liver problems. They were administered as decoction, paste, vapor inhalation, fruit juice, and poultice. The RFC, FC, UR, and CI values of the NUCs were in the range of 12 to 365, 0.03 to 0.82, 12 to 394, and 0.03 to 0.89, respectively. Fruits were the most commonly consumed part, followed by leaves, tubers, pods, and aerial bulbs, whereas the mode of consumption was stir-fry, soup, vegetables, salad, or in raw form. NUCs were bestowed with essential macro- and micronutrients and were found in the range of Ca (3.79–1147.3), K (2.6–1600.3), Mg (0.8–468.0), Na (0.4–270.8), P (1.15–305), Fe (0.1–327.6), Zn (0.1–84.6), Cu (0.047–33.3), Mn (0.1–62.3) mg/100 g, and vitamins like ascorbic acid (0.04–1561.1), thiamine (0.041–2.4), and β-Carotene (0.2–93.6) mg/100 g. These NUCs were cultivated in different settings, such as kitchen gardens, backyard gardens, border crops, and sometimes agricultural fields. The current study reveals the rich diversity and varied use of these NUCs with respect to their ethnomedicinal, nutritional, and agricultural relevance. Sustainable utilization with large-scale cultivation of promising NUCs can lead to local food security and the subsequent attainment of the associated UN Sustainable Development Goals.