The regulatory mechanisms for inflammatory response in the heart to endotoxin, which causes severe cardiac dysfunction, are not fully understood. We hypothesized the involvement of coxsackie and adenovirus receptor (CXADR), which can promote tissue inflammation by potentiating cell-cell adhesion, independent of viral infection, and examined the role of CXADR in endotoxin-induced cardiac dysfunction and its mechanism using an experimental mouse model. Conditional whole-body and endothelium-specific CXADR knockout (W-KO and E-KO, respectively) mice were generated using the Cre-loxP system and administered lipopolysaccharide (LPS) or vehicle alone, like wild-type (WT) mice. Cardiac CXADR increased 12 h after LPS challenge in WT mice, along with improved cardiac dysfunction and reduced cardiac expression of interleukin (IL)-6 and IL-1β. Moreover, W-KO in adult mice worsened cardiac dysfunction and increased expression of these cytokines. Meanwhile, E-KO exhibited the opposite effects, concomitantly reducing myocardial inflammation. Bulk RNA sequencing analysis identified an enriched IL-17 A signaling pathway capable of inducing IL-6 and IL-1β expression in the heart 12 h after LPS challenge. In this heart, E-KO attenuated phosphorylation of p38 but not of upstream mitogen-activated protein kinase kinase (MKK)3/6. Conversely, W-KO augmented phosphorylation of p38, MKK3/6, and NF-κB/p65, which are key drivers of the IL-17 A signaling. Our study is the first to demonstrate that increased CXADR expression plays a dual role as both a pro-inflammatory mediator and an anti-inflammatory protector in endotoxin-induced cardiac dysfunction, possibly by positively or negatively regulating p38 activation depending on its cellular origin. Targeted manipulation of CXADR expression may provide clinical benefits.