Morphine is a poor inducer of μ‐opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [d‐Ala²‐MePhe⁴‐Gly‐ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy‐terminal residue 375 (Ser³⁷⁵). Ser³⁷⁵ phosphorylation was sufficient and required for morphine‐induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO‐desensitized receptors were rapidly dephosphorylated. In contrast, morphine‐desensitized receptors remained at the plasma membrane in a Ser³⁷⁵‐phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser³⁷⁵.