We have previously demonstrated that STAT3 hyperactivation via the interleukin 6 (IL-6) cytokine family receptor gp130 in gp130^Y757F/Y757F mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Because IL-6 and IL-11 both signal via a gp130 homodimer, we report here a genetic approach to dissect their individual roles in these pathologies. Neutrophilia and thrombocytosis were absent in gp130^Y757F/Y757F mice lacking either IL-6 (gp130^Y757F/Y757F: IL-6^−/−) or the IL-11 receptor α subunit (gp130^Y757F/Y757F: IL-11Rα1^−/−), and this was associated with a normalized bone marrow compartment. The elevated myelopoiesis and megakaryopoiesis in bone marrow of gp130^Y757F/Y757F mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor β (TGF-β) signaling, which is a suppressor of these lineages. In contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130^Y757F/Y757F mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6Rα, and IL-6Rα expression was reduced in gp130^Y757F/Y757F: Stat3^+/− mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathologic hematopoietic and lymphoid responses mediated by STAT3 hyperactivation.