All lattice-QCD calculations of the hadronic-vacuum-polarization contribution to the muon’s anomalous magnetic moment to date have been performed with degenerate up- and down-quark masses. Here we calculate directly the strong-isospin-breaking correction to aμHVP for the first time with physical values of mu and md and dynamical u, d, s, and c quarks, thereby removing this important source of systematic uncertainty. We obtain a relative shift to be applied to lattice-QCD results obtained with degenerate light-quark masses of δaμHVP,mu≠md=+1.5(7)%, in agreement with estimates from phenomenology.