This Special Issue publishes original papers that contribute to Decision Support Systems’ Innovation and Uncertainty Management in Agri-Food Systems. Of particular interest to this issue are works that approach the topic with a perspective on sustainability, relying on a socio-technical contribution where human and social ingredients are important. The issue also includes high-quality revised papers, selected, and extended from the RUC- APS International Conference “Enhancing and implementing Knowledge-based ICT solutions within high risk and Uncertain Conditions for Agriculture Production Systems,” held online, between 29 November and 2 December 2021. This editorial con-tains a brief overview of the seven research articles submitted by the international community.