We synthesized polymeric prodrugs in which ibuprofen (IBU) was conjugated in a one-pot preparation to the hydrophilic polysaccharide hydroxyethylcellulose (HEC). The amphiphilic conjugates formed nanoparticles of 450–700 nm diameter at a water/DMSO interface. Synthesized HEC-IBU conjugates showed significant anti-inflammatory (44–77% inhibition) and immunomodulatory potential in paw-edema and cytokine release assays, respectively. Cell viability studies on L929 cell lines were performed for HEC-IBU prodrugs. Pharmacokinetic studies in rabbit models revealed that IBU from the conjugate reaches a peak plasma concentration (C_max) of 20 μg mL⁻¹ in 4 h while the plasma half-life was noted to be 5.82 h μg mL⁻¹.