Protein tyrosine phosphatase non-receptor type 1 (PTPN1) is a crucial regulator of insulin and leptin signaling pathways, positioning it as a promising therapeutic target for the development of insulin sensitizers in the treatment of type 2 diabetes mellitus (T2DM). Our previous studies demonstrated that lipidated/acylated BimBH3 core peptide analogues function as potent PTPN1 inhibitors with potential for once-weekly hypoglycemic efficacy. Additionally, alanine scanning identified specific residues that could be modified without compromising inhibitory activity. In this study, we designed and synthesized 14 lipidated BimBH3 analogues incorporating d-amino acids through site-specific modifications to enhance peptide stability and activity. Among these, analogues D-1, D-9, D-10, D-11, D-12, and D-14 exhibited potent PTPN1 inhibitory activity, demonstrated significant resistance to proteolytic degradation, and showed good stability in mouse plasma. Notably, in glucose tolerance tests, subcutaneous administration of D-14 led to a significant 26.2 % reduction in blood glucose (AUC0-120 min), while oral administration achieved a 15.4 % reduction (AUC0-180 min), indicating promising oral bioavailability. Further analysis using molecular docking and kinetic studies confirmed the strong binding affinity of d-amino acid-containing BimBH3 analogues for PTPN1, supporting their potential for sustained hypoglycemic effects. Overall, our findings demonstrate that the dual modifications of d-amino acid substitution and lipid conjugation significantly enhance the inhibitory activity, bio-stability, and oral availability of BimBH3 analogues, highlighting their potential as novel, long-acting therapeutics for T2DM management.