Industrial agriculture driven by a capital-centric growth model has become both the culprit and the victim of burgeoning socioecological footprints such as air and water pollution, land degradation, loss of biodiversity, climate change, food heteronomy, and socioeconomic disparity. The chronically perturbed agrifood and livelihood systems in Nepal are also clear manifestations of the discordance between delusively imitated development policies and the on-the-ground realities typified by geophysical and socioeconomic contexts. This chapter posits a comprehensive perspective and operational framework for agriculture-based socioecological transformation. The perspective and framework assimilate both a modern agroecological paradigm and South Asian eco-spiritual wisdom that pertains to agrarian economy and livelihood systems globally in general, and specifically in Nepal. We reviewed both modern agroecological and sanatana (a unified philosophy based on universal and primordial truths) literature and assembled cultural wisdom from authors’ own recollections and conversations with knowledgeable key informants. We articulate Nepal’s geographical and socioeconomic realities that dictate a self-reliant, sovereign agriculture-based economy in line with the emerging agroecological paradigm and time-tested traditional wisdom. In view of these realities, we advance the framework for a prudent, eco-friendly systems approach to managing space (S1), species (S2), seeds and breeds (S3), soils and water (S4), seasonality (S5), and stress factors (S6) with the deployment of supportive infrastructure and institutional services (S7) to develop a self-regulatory synergistic agrifood system (S8) that justifies socioeconomic objectivity (S9) and socioecological symbiosis (S10). This “S-10” operational framework covers ontological, epistemological, and axiological aspects with clear courses of action, efficient processes, and rational outcomes based on socioecological and eco-spiritual values. It identifies diverse areas for leveraging interventions and policy imperatives for the resilient and regenerative agrifood systems across hierarchical scales from farms to nation, traversing through a rural to urban gradient.