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Lettuce (Lactuca sativa L.) is an annual leafy vegetable crop from the Asteraceae family with the possibility to grow all year round. Two lettuce cultivars (red 'Murai' and green 'Aleppo') were cultivated in a greenhouse using two biofertilizers (a mixture of different effective microorganisms and Trichoderma spp. fertilizer), and their combination, during three consecutive growing seasons. This study aimed to find the optimal combination of fertilization treatments and growing seasons depending on different production criteria, using a multi-criteria decision-making (MCDM) method, Measurement of Alternatives and Ranking according to COmpromise Solution (MARCOS). A total number of 12 lettuce production models (alternatives) were proposed regarding fertilization treatments and planting dates. The study analyzed 12 criteria, which were divided into three groups: quantity, quality, and economic criteria. Weight coefficients were determined using the Analytic Hierarchy Process (AHP) method while, the stability of the obtained ranking list was investigated by applying comparative analysis using four other MCDM methods, as well as by performing sensitivity analysis through four scenarios. Cultivar 'Murai' showed the best results in the winter growing season with the application of Trichoderma spp. fertilizer, while cultivar 'Aleppo' in the spring with the combined fertilizers (effective microorganisms + Trichoderma spp). This study supports farmers and agricultural companies in optimizing planting schedules and biofertilizer selectiontailored to specific cultivars, integrating quantity, quality, and economic criteria to enhance productivity and sustainability. Furthermore, it reveals the significant role of cultivar choice in optimizing biofertilizer type and growing season selection for lettuce production, demonstrating the MARCOS method’s robustness as a decision-support tool in agricultural planning and management.