Abstract Body (Do not enter title and authors here): Introduction: Noise exposure is increasingly recognized as a significant contributor to cardiovascular disease (CVD). Clinical and epidemiological studies have demonstrated that noise increases stress hormones, such as cortisol and adrenaline, induces oxidative stress. Chronic exposure is associated with higher blood pressure, and a greater incidence of heart failure, with a 2–8% increase in risk for every 10 dB increase in noise levels. Beyond its direct cardiovascular effects, environmental noise disrupts sleep. It fragments sleep architecture by increasing wakefulness and stage 1 sleep while reducing restorative REM sleep. Since sleep regulates neuroendocrine, inflammatory, and metabolic homeostasis, its disruption can amplify CVD risk. Despite these associations, the molecular mechanisms linking noise and sleep disruption to cardiac dysfunction remain poorly understood. Hypothesis: We hypothesized that exposure to a combination of stressors, namely noise and sleep deprivation, activates the NLRP3 inflammasome via endoplasmic reticulum (ER) stress, thereby amplifying inflammation and contributing to adverse cardiac remodeling. Methods: CBA-CaJ and C57BL/6 mice were exposed to 80 dB SPL noise for 8 hours/day over 10 days during the light phase to induce sleep disruption. We assessed cardiac function and remodeling using echocardiography, flow cytometry, and molecular analyses. Results: Noise-exposed mice showed significantly reduced ejection fraction and altered E/A ratios, indicating both systolic and diastolic dysfunction. We noted increased LV mass, heart rate, blood pressure, plasma corticosterone levels, atrial natriuretic peptide A expression, and inflammatory cytokine levels. Flow cytometry of single cardiac cells and analyses of cardiac tissue confirmed NLRP3 inflammasome during the priming and triggering stages. Additionally, ER stress markers, including BiP, XBP1, CHOP, phosphorylated-p38, p-eIF2α, and PERK, were significantly elevated in noise-exposed hearts. In vitro, hiPSC-cardiomyocytes treated with 4-PBA and TUDCA (ER stress inhibitors) displayed reduced levels of NLRP3, ASC, caspase-1, and IL-1β, establishing a causal link between ER stress and inflammasome activation. Conclusions: Our findings reveal a novel mechanistic pathway linking environmental stressors to cardiac dysfunction. Targeting endoplasmic reticulum stress may provide new therapeutic strategies to reduce inflammation-driven heart disease in noise-exposed populations.