<p>Designing highly active, cost-effective, stable, and coke-resistant catalysts is a hurdle in commercializing bio-oil steam reforming. Single-atom alloys (SAAs) are captivating atomic ensembles crosschecking affordability and activity, yet their stability is held questionable by trial-and-error synthesis practices. Herein, we employ descriptor-based density functional theory (DFT) calculations to elucidate the stability, activity, and regeneration of Ni-based SAA catalysts for acetic acid dehydrogenation. While 12 bimetallic candidates pass the cost/stability screening, they uncover varying dehydrogenation reactivity and selectivity, introduced by favoring different acetic acid adsorption modes on the SAA sites. We find that Pd-Ni catalyst provokes the utmost H₂ activity, however, ab-initio molecular simulations at 873 K reveals the ability of Cu-Ni site to effectively desorb hydrogen compared to Pd-Ni and Ni, attributed to the narrowed surface charge depletion region. Notably, this Cu-Ni performance is coupled with enhancing C^*-gasification and acetic acid dehydrogenation with respect to Ni. Building upon these findings, DFT-screening of trimetallic M₁-M₂-Ni co-dopants recognizes 6 novel modulated single-sites with high stability, balanced H^*-adsorption, and anti-coking susceptibility. This work provides invaluable data to accelerate the discovery of affordable and efficient <i>bimetallic</i> and <i>trimetallic</i> SAA catalysts for bio-oil upgrading to green hydrogen.</p>