Dendritic spines are morphologically and functionally heterogeneous. Here, we use two-photon imaging of layer V pyramidal neurons in slices from mouse visual cortex to characterize differences in spine calcium dynamics between individual spines. By measuring action potential-evoked [Ca2+]i transients in spines, we find different calcium dynamics in spines from proximal apical and distal apical dendrites. Using a mathematical multi-compartmental model, we demonstrate that these differences are even more pronounced in the absence of exogenous calcium buffers. We also find that these different calcium dynamics cause different susceptibility to synaptic depression in proximal and distal apical synapses, and that modifying calcium decay kinetics in spines changes the expression of long-term depression. We conclude that the location of the spine determines its time window of calcium compartmentalization and degree of calcium-dependent synaptic plasticity. Our results highlight the precision of the design of neocortical neurons.