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Interleukin 6 (IL‐6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal‐transducing element gp130 through ligation of either the membrane‐bound or soluble IL‐6 receptor (termed classic and trans‐signaling respectively). It has been proposed that selective inhibition of trans‐IL‐6 signaling could ameliorate the deleterious, pro‐inflammatory effects of IL‐6, while preserving the homeostatic activity of classic IL‐6 signaling. We developed an in silico, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans‐IL‐6 signaling. In the first stage, we developed a limited‐scope model of IL‐6 signaling to establish the quantitative properties of classic and trans‐signaling pathways on a short timescale following stimulation with IL‐6. The model included both a pan‐inhibitor of IL‐6 classic and trans‐signaling and a soluble gp130‐Fc that selectively inhibited trans‐signaling. In the second stage, we developed a multi‐scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL‐6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi‐scale model, we identified a dose–response relationship between selective inhibition of trans‐IL‐6 signaling and tissue regeneration. Moreover, selective inhibition of trans‐IL‐6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL‐6 suppression. These findings suggest that global suppression of IL‐6 signaling could negatively affect IL‐6‐induced regeneration activity, whereas this effect is less likely for selective inhibition.