The present study aimed to test a multipurpose sustainable tobacco farming system allowing more efficient use of production factors (e.g., mineral N fertilizer) thanks to larger commercial yields, albeit diversified (smoke products, bioactive compounds for nutraceutical and cosmeceutical uses, energy), per unit of land area. Three tobacco types (dark air-cured, IBG; light air-cured, Bu; dark fire-cured, Ky) were grown in the field in 2021 on three different soils (sandy clay loam, SCL; sandy loam, SL; clay loam, CL). The total waste biomass (WB, kg dry weight, d.w. ha−1) was measured. Commercial leaves yield (CLY, kg d.w. ha−1), N agronomic efficiency (NAE, kg d.w. kg−1 N), total polyphenols content (TP, mg kg−1 d.w.), antioxidant activity (ABTS, DPPH and FRAP, mmol Trolox Equivalent, TE, kg−1 d.w.) and yield of polyphenols (PY, kg ha−1) were determined. The calorific value (CV, MJ kg−1 d.w.), volatile matter (VM, %) and ash contents (%) were also measured, and biomass energy yield (BEY, GJ ha−1 yr−1) was then calculated. Very high percentages (>40%) of total biomass produced by the different tobacco types were pre-harvest waste. NAE increased by 2- to more than 8-fold thanks to a greater potential commercial biomass produced with the same amount of N fertilizer used. Four main components were found in the tobacco polyphenols profile, namely 3-O-CQA, luteolin 7 rutinoside, rutin and quinic acid, which accounted for more than 80% of TP. BEY ranged between 122.3 GJ ha−1 yr−1 (Bu) and 29.9 GJ ha−1 yr−1 (Ky). Both polyphenols yield and energy potential per unit land area and/or per growing season appeared competitive with those from other herbaceous crops. The proposed multipurpose system appeared as a production circuit characterized by a virtuous and sustainable flow of resources.