Background <p>Zhen-Wu-Tang (ZWT), a classic herbal formula from Treatise on Febrile and Miscellaneous Diseases, is commonly used for heart and kidney-related diseases. Despite its widespread application, research on the active components of ZWT and their mechanisms in heart–kidney cross-organ regulation remains underexplored.</p> Aim of the study <p>This study aimed to elucidate the therapeutic mechanisms of ZWT in uremic cardiomyopathy (UC) focusing on its modulation of the heart–kidney inflammatory axis.</p> Materials and methods <p>A UC model was established via 5/6 nephrectomy in mice, followed by 8&#xa0;weeks of ZWT treatment. Functional assessments included serum creatinine, blood urea nitrogen, cardiac ejection fraction, and left ventricular metrics. Proteomic analysis using Olink technology exerts its therapeutic effects by suppressing systemic inflammation. UHPLC-Q/TOF–MS were employed to identify prototype components and blood-entering components in ZWT. Cellular experiments using a three-step co-culture system were conducted to evaluate the regulatory effects of ZWT active components on HK-2 and AC16 cells and to explore their underlying molecular mechanisms.</p> Results <p>ZWT significantly improved renal and cardiac functions. Proteomics revealed ZWT suppressed pro-inflammatory cytokines TNFα, IL-6, IL-1β and chemokines. The bioactive constituents of ZWT, including benzoylaconine, paeoniflorin, and atractylenolide III, inhibited NF-κB activation, thereby reducing CCL2 synthesis and subsequent macrophage recruitment via the CCR2 axis. This attenuated systemic inflammation and cardiomyocyte injury.</p> Conclusions <p>ZWT exerts therapeutic effects on UC by targeting the kidney-heart inflammatory axis and suppressing CCL2/CCR2-mediated macrophage activation. This study provides new insights into the molecular mechanisms underlying ZWT's efficacy in treating heart–kidney disorders.</p>