To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ receptor (σR) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K = 6.5 nΜ; EC = 48.5 nΜ, E = 66.3%) and σR antagonism (K = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED = 0.30 mg/kg, in mice). The contributions of MOR and σR to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σR agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σR ligands as a promising avenue for the development of potent and safe analgesics.