Circulating levels of interleukin (IL)‐6 are elevated after myocardial infarction (MI) and associated with increased morbidity and mortality. Its myocardial expression post‐MI suggests a pathophysiological role in this condition. To explore the role of endogenous IL‐6, we analyzed MI size, left ventricular (LV) remodeling, and mortality after permanent coronary ligation in IL‐6 knockout mice (IL‐6^−/−) and wild‐type controls (WT). Six weeks after MI, IL‐6^−/− and WT had similar mortality rates, MI sizes, LV remodeling, and LV dysfunction in vivo, determined by catheterization. Infarct size 24 h post‐MI, shown by 2,3,5‐triphenyltetrazolium chloride (TTC) staining, was similar at 24 h. Treatment with exogenous IL‐6 did not alter MI size in WT. Infarction resulted in marked phosphorylation of STAT3, without differences between genotypes. Leukemia inhibitory factor (LIF) protein was increased 48 h post‐MI in IL‐6^−/−, and angiotensin II and AT₁ receptor (AT₁R) protein were strongly increased in IL‐6^−/− baseline and post‐MI, suggesting compensatory up‐regulation. Lack of IL‐6 does not affect long‐term MI size or LV function, remodeling, and survival. In mice lacking IL‐6, other members of the IL‐6 family such as LIF and other factors signaling via JAK/STAT such as angiotensin may act in a compensatory manner to activate the JAK/STAT pathway, thereby maintaining STAT3 phosphorylation, which is crucial for the cellular effects of IL‐6 cytokines.