Saffron (Crocus sativus L.) stands as a valuable agricultural commodity, witnessing an increasing market inclination toward environmentally sustainable and eco-friendly products. The current literature on the environmental impact and profitability of saffron cultivation is limited, underscoring a notable gap in comprehending the sustainability aspects of this crop. This study utilized a comprehensive multi-model approach to assess the sustainability of annual saffron cultivation, representing the first global detailed evaluation, conducted within a European context (Southern Italy). Energy analysis, physical and monetized life cycle assessment (LCA), and life cycle costing (LCC) were used for a cradle-to-farm gate assessment. One hectare of cultivated saffron, one saffron production yield (stigma, corm, and flower), and 1 kg of stigma yield were used as functional units. The total energy input was 65,073 MJ ha−1, being 33% direct, 67% indirect, 72% renewable, and 28% non-renewable. The majority (55%) of energy is derived from corm production. For 1 kg of saffron the energy efficiency, specific energy, and productivity were 2.98, 4.64 MJ kg−1, and 0.22 kg MJ−1, respectively, while these values dropped significantly for 1 kg of stigma. The multi-indicator LCA analysis using the ReCiPe 2016 model revealed significant contributions to various environmental impact categories. Results align with prior research, pinpointing fertilization and mechanical operations as the primary drivers of diverse environmental impacts. A noticeable carbon intensity was estimated, with a relevant contribution from corm production and human labor, aspects overlooked in previous LCA studies. Saffron cultivation maintains economic viability, with production costs at EUR 98,435 per ha−1 and a net return margin of EUR 172,680 per ha−1, bolstered by the high market price and by-product revenue. Monetization of LCA results revealed that external costs were EUR 15,509 per ha−1, being only 14% of the total cost. Investments in improving yield and resource efficiency have the potential to increase the eco-efficiency of saffron cultivation.