The management of chronic pain remains one of the greatest challenges of the 21st century, affecting over a third of the world’s population, and yet it is often not treated appropriately. To address this important public health issue, dual-target ligands that can engage more than one receptor and exert complementary analgesic actions represent a promising avenue for the treatment of acute and chronic pain. Therefore, ligands acting on the neurotensin receptor type 2 (NTSR2), which exert non-opioid antinociceptive effects and a synergistic effect when co-administered with opioids, offer an attractive option for being fused to an opioid pharmacophore. To this end, a series of opioid-neurotensin hybrid ligands was rationally designed by combining various derivatives of the opioid tetrapeptide H-Dmt-D-Arg-Aba-b-Ala-NH2, with the NTSR2-selective NT(8-13) analogs of H-Arg-Arg-Pro-(6-OH)Tic-Tle-Leu-OH. All chimeric peptides, which exhibited high plasma stability (> 7 h), showed high affinity for NTSR2 (1 to 5 nM), good selectivity over NTSR1 (Ki > 1800 nM), MOP affinity values in the sub-nanomolar range (< 1 nM) and DOP affinity values in the nanomolar range (20 to 176 nM). In BRET-based biosensors assays, all hybrids behaved as full agonists in activating the Gi response and as full or partial agonists in recruiting b-arrestin-2 to MOP. Finally, their analgesic efficacy, assessed using acute, tonic, post-operative, and chronic pain models, revealed a strong analgesic effect after intrathecal or intravenous administration. Altogether, these bifunctional ligands represent a promising avenue towards the development of safer analgesics with improved efficacy and reduced side-effect profiles.