Sepsis, a life-threatening condition triggered by an uncontrolled immune response to infection, currently lacks an FDA-approved therapeutic intervention to enhance patient survival. Severe inflammatory conditions can disrupt the balance of histone acetyltransferase (HAT)/histone deacetylase (HDAC) activity, leading to global cellular hypoacetylation. Histone deacetylase inhibitors (HDACi) restore acetylation profiles and reverse transcriptional silencing. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, was modified by para-hydroxymethylation (termed SAHA-OH), which resulted in a favourable reduction in SAHA-associated toxicity under inflammatory lipopolysaccharide (LPS) challenge. SAHA-OH was incorporated into immunomodulatory nanoparticles (iNPs), previously developed by our lab, to form iNP-SAHA using a prodrug approach through the covalent modification with poly(lactic-co-glycolic acid) (PLGA). iNP-SAHA treatment significantly reduced proinflammatory cytokines in vitro and in vivo, improved the viability of LPS-stimulated primary macrophages, and enhanced survival of mice in an LPS-induced endotoxemia model. iNP-SAHA treatment did not significantly improved mice survival compared to the iNP treatment alone; however, the synergistic anti-inflammatory properties of iNP-SAHA are potentially promising for future exploration in alternative models of inflammatory disease. We evaluated the efficacy and cellular mechanism of iNP activity using a clinically relevant cecal ligation and puncture (CLP) murine model of polymicrobial sepsis. iNPs, when administered as an adjuvant to antibiotics, significantly improved survival compared to antibiotics alone. Interestingly, iNP treatment marginally affected local and systemic cytokine profiles, despite mitigating organ dysregulation. Minimal effects on immune cell proportions at local sites were observed, but iNP treatment normalized monocyte levels in peripheral blood and alveolar macrophages in lung tissues. Further studies enumerated that iNPs modulated cellular adhesion and migration surface marker expression as well as apoptotic levels on immune cells. These findings highlight the potential of iNPs as an adjunctive therapy for sepsis, particularly when combined with antibiotics, suggesting promising prospects for future clinical translation. Lastly, a high-throughput microfluidic approach for iNP formulation to enable facile scale-up was developed. We optimized the microfluidic method and the impact of polymer and surfactant concentrations, surfactant chemistry, flow rate ratio (FRR), and anti-inflammatory activity. This work demonstrated a controlled and reproducible microfluidic method for iNP formulation, showcasing their inherent anti-inflammatory properties and offering a promising avenue for inflammation management.