This study was performed to investigate the liposome coated colistin for enhancing the oral pharmacokinetics, bioavailability, delivery and efficacy of the drug against resistant E. coli strain. Minimum inhibitory concentration (MIC) of colistin and liposomal colistin (LC) was 1.56 µg/ml and 0.00156 µg/ml for O125 sensitive colistin strain, while 100µg/ml and 0.025 µg/ml for O125 resistant strain. In vitro, time kill kinetics of LC against sensitive and resistant O125 recorded 100% and 82.8% as a reduction %at 1 MIC, while ≥99.9% at 2 MIC for both strains after 1hr incubation time. The pharmacokinetic/pharmacodynamics profiles were studied by single oral dose of colistin and LC at 100000 IU/kg b.wt in healthy and diseased chicken. Liver E. coli was counted after repeated treatment for 5 consecutive days. The pharmacokinetic parameters; Cmax/MIC ratio for colistin against both strains were 3.5 and 0.06. While, LC recorded 3.9x10³ and 247.2, respectively. AUC/MIC ratios were 13.4, 0.248, 40.9x10³ and 2.6x10³, respectively; proving the high efficacy of LC with less significant activity of colistin. There was significant increment of t_1/2 Beta and MRT of LC groups in comparison with colistin groups. Contraries, clearance Time (V/F) was significantly decreased in LC than colistin groups. LC enhanced the bioavailability% from 5.2% to 49.2%. Liver E. coli count revealed highly significant decrease of LC for both strains nearly similar to negative control group; indicating the great effect of LC on both E. coli strains especially for colistin resistant strain. This study recommends the liposomal colistin formulation against multidrug resistant E. coli infections.