The production of a biomass as a feedstock for biorefinery is gaining attention in many agricultural areas. The adoption of biorefinery crops (i.e., perennial cardoon) can represent an interesting option for farmers and can contribute to increase soil organic carbon stock (SOCS). The study aimed to assess the potential effect on long-term SOCS change by the introduction of cardoon in a Mediterranean marginal area (Sassari, Italy). To this end, three process-oriented models, namely the Intergovernmental Panel on Climate Change (IPCC) guidelines for national greenhouse gas inventories (Tier 2), a humus-balance model (SOMBIT) and Rothamsted carbon model (RothC), were used to compare two scenarios over 20 years. The traditional cropping system’s faba bean–durum wheat biennial rotation was compared with the same scenario alternating seven years of cardoon cultivation. The model’s calibration was performed using climate, soil and crop data measured in three cardoon trials between 2011 and 2019. SOMBIT and Roth C models showed the best values of model performance metrics. By the insertion of cardoon, IPCC tool, SOMBIT and RothC models predicted an average annual SOCS increase, whereas, in the baseline scenario, the models predicted a steady state or a slight SOCS decrease. This increase can be attributed to a higher input of above - and belowground plant residues and a lower number of bare soil days (41 vs. 146 days year−1).