Macrophage plasticity has been studied in vitro, but transcriptional regulation upon injury is poorly understood. We generated a valuable dataset that captures transcriptional changes in the healthy heart and after myocardial injury, revealing a dynamic transcriptional landscape of macrophage activation. Partial deconvolution suggested that post-injury macrophages exhibit overlapping activation of pro-inflammatory and anti-inflammatory programs rather than aligning to canonical M1/M2 programs. Furthermore, simulated dynamics and experimental validation of a regulatory core of the underlying gene-regulatory network revealed a negative-feedback loop that limits initial inflammation via hypoxia-mediated upregulation of Il10. Our results also highlight the prominence of post-transcriptional regulation (miRNAs, mRNA decay, and lincRNAs) in attenuating the myocardial injury-induced inflammatory response. We also identified a cardiac-macrophage-specific gene signature (e.g., Egfr and Lifr) and time-specific markers for macrophage populations (e.g., Lyve1, Cd40, and Mrc1). Altogether, these data provide a core resource for deciphering the transcriptional network in cardiac macrophages in vivo.