Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease with limited therapeutic options. Interleukin-22 (IL-22) has shown promise in preclinical models of diabetes by suppressing β-cell stress, reducing islet inflammation, and improving insulin production. However, long-acting forms of IL-22 have led to adverse effects such as increased proliferation in the skin and intestine. To address these issues, we designed short-acting IL-22-bispecific biologics that target the liver and pancreas. These targeted biologics demonstrated 10-fold lower doses than native IL-22, achieving beneficial effects in multiple preclinical models of MASH without off-target effects. Treatment restored glycemic control, reduced hepatic steatosis, inflammation, and fibrosis. The short-acting IL-22-bispecific biologics show promise as a new therapeutic approach for MASH.Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease with limited therapeutic options. Interleukin-22 (IL-22) has shown promise in preclinical models of diabetes by suppressing β-cell stress, reducing islet inflammation, and improving insulin production. However, long-acting forms of IL-22 have led to adverse effects such as increased proliferation in the skin and intestine. To address these issues, we designed short-acting IL-22-bispecific biologics that target the liver and pancreas. These targeted biologics demonstrated 10-fold lower doses than native IL-22, achieving beneficial effects in multiple preclinical models of MASH without off-target effects. Treatment restored glycemic control, reduced hepatic steatosis, inflammation, and fibrosis. The short-acting IL-22-bispecific biologics show promise as a new therapeutic approach for MASH.