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Summary: Background: Macrophage infiltration and polarization are integral to the progression of heart failure and cardiac fibrosis after ischemia/reperfusion (IR). Interleukin 34 (IL-34) is an inflammatory regulator related to a series of autoimmune diseases. Whether IL-34 mediates inflammatory responses and contributes to cardiac remodeling and heart failure post-IR remains unclear. Methods: IL-34 knock-out mice were used to determine the role of IL-34 on cardiac remodeling after IR surgery. Then, immunofluorescence, flow cytometry assays, and RNA-seq analysis were performed to explore the underlying mechanisms of IL-34-induced macrophage recruitment and polarization, and further heart failure after IR. Findings: By re-analyzing single-cell RNA-seq and single-nucleus RNA-seq data of murine and human ischemic hearts, we showed that IL-34 expression was upregulated after IR. IL-34 knockout mitigated cardiac remodeling, cardiac dysfunction, and fibrosis after IR and vice versa. RNA-seq analysis revealed that IL-34 deletion correlated negatively with immune responses and chemotaxis after IR injury. Consistently, immunofluorescence and flow cytometry assays demonstrated that IL-34 deletion attenuated macrophage recruitment and CCR2+ macrophage polarization. Mechanistically, IL-34 deficiency repressed both the canonical and noncanonical NF-κB signaling pathway, leading to marked reduction of P-IKKβ and P-IκBα kinase levels; downregulation of NF-κB p65, RelB, and p52 expression, which drove the decline in chemokine CCL2 expression. Finally, IL-34 and CCL2 levels were increased in the serum of acute coronary syndrome patients, with a positive correlation between circulating IL-34 and CCL2 levels in clinical patients. Interpretation: In conclusion, IL-34 sustains NF-κB pathway activation to elicit increased CCL2 expression, which contributes to macrophage recruitment and polarization, and subsequently exacerbates cardiac remodeling and heart failure post-IR. Strategies targeting IL-34-centered immunomodulation may provide new therapeutic approaches to prevent and reverse cardiac remodeling and heart failure in clinical MI patients after percutaneous coronary intervention. Funding: This study was supported by the National Nature Science Foundation of China (81670352 and 81970327 to R T, 82000368 to Q F).