The sustainable production of leafy crops is particularly important in Mediterranean regions, where water scarcity and the nutrient unbalance in soil-plant systems are common. Intensive crop production under these edaphoclimatic conditions is typically basedon conventional agriculturewith high inputs and limited incorporation of organic matter, and has a significant impact on natural resources and greenhouse gas (GHG) emissions. This study evaluated various fertilisation strategies in a Calcaric Fluvisol under warm semi-arid conditions in south-east Spain. The experiment followed a completely randomised design with three replicates and five fertilisation treatments: (i) organic treatments (cattle manure [CM] and two agri-food waste derived composts [X1B and X2C]); (ii) inorganic treatments (mineral fertiliser NPK [IN] and NPK fertiliser with a nitrification inhibitor [LI2]), all of which were applied at a rate of 150 kg N ha-1 during the lettuce crop cycle and soil plots without treatment were used as control treatment (B). GHG emissions and UAV-based multispectral vegetation indexes were measured after fertiliser applications and at the harvest, while soil properties and lettuce yield were determined at the end of the experiment. Mineral fertilisers produced the highest lettuce yields (73.8 and 82.4 Mg ha-1 for IN and LI2, respectively), while X1B compost achieved a similar yield to IN. The organic fertilisation (X1B and X2C) significantly increased soil organic carbon (C), with X1B showing a 14% increase from initial values. They also resulted in the lowest total GHG emissions (19-26 kg ha-1 CO2eq), compared to the inorganic treatments (68-67 kg ha-1 CO2eq). UAV-derived vegetation indices distinguished between fertilisation strategies and correlated strongly with yield. Using compost-based organic fertilisation can sustain competitive lettuce yields while improving soil health, balancing nutrients and reducing GHG emissions. In water-limited Mediterranean systems, this approach provides a practical way to make agriculture more resilient and climate-smart, while ensuring productivity is aligned with environmental sustainability.