The molecular mechanisms responsible for the ‘distal’ effect by which noradrenaline (NA) blocks exocytosis in the β‐cell were examined by whole‐cell and cell‐attached patch clamp capacitance measurements in INS 832/13 β‐cells. NA inhibited Ca²⁺‐evoked exocytosis by reducing the number of exocytotic events, without modifying vesicle size. Fusion pore properties also were unaffected. NA‐induced inhibition of exocytosis was abolished by a high level of Ca²⁺ influx, by intracellular application of antibodies against the G protein subunit Gβ and was mimicked by the myristoylated βγ‐binding/activating peptide mSIRK. NA‐induced inhibition was also abolished by treatment with BoNT/A, which cleaves the C‐terminal nine amino acids of SNAP‐25, and also by a SNAP‐25 C‐terminal‐blocking peptide containing the BoNT/A cleavage site. These data indicate that inhibition of exocytosis by NA is downstream of increased [Ca²⁺]_i and is mediated by an interaction between Gβγ and the C‐terminus of SNAP‐25, as is the case for inhibition of neurotransmitter release. Remarkably, in the course of this work, a novel effect of NA was discovered. NA induced a marked retardation of the rate of refilling of the readily releasable pool (RRP) of secretory granules. This retardation was specifically abolished by a Gα_i1/2 blocking peptide demonstrating that the effect is mediated via activation of Gα_i1 and/or Gα_i2.