The current study aims to improve clarithromycin bioavailability and effectiveness in complicated intra-abdominal infection management. Therefore, clarithromycin-loaded submicron dual lipid carriers (CLA-DLCs) were developed via hot high shear homogenization technique and evaluated for colloidal parameters, release behavior, stability study, and in-vitro antibiofilm activity. Bioavailability and therapeutic efficacy of optimized formulation on hampering cytokines storm induction was determined inE. coli-induced peritonitis. The developed CLA-DLCs (particle size 326.19 ± 24.14 nm, zeta potential −31.34 ± 2.81 mV, and entrapment efficiency 85.78 ± 4.01%) exhibited smooth spherical shapes and sustained in vitro release profiles. Long-term stability study of optimized CLA-DLCs ensured maintenance of colloidal parameters for 1 year at room temperature. In vitro antimicrobial studies revealed 3.43-fold higher anti-biofilm activity of CLA-DLCs compared with clarithromycin. In addition, the relative bioavailability of CLA-DLCs was enhanced 5.89-fold compared to pure drug in rats. The remarkable decrease in microbial burden in blood as well as tissues, along with oxidative stress markers (lipid peroxidation, myeloperoxidase activity, and carbonylated protein level) and immunological markers (total leukocyte count, neutrophil migration, NO, TNF-, and IL-6) on treatment with CLA-DLCs enhanced the survival in a rat model of peritonitis compared with the pure drug and untreated groups. In conclusion, CLA-DLCs hold promising potential in management of intra-abdominal infections and prevention of associated complications.