Calcined clays can be potential supplementary cementitious materials if effects of heat-treatment on their structure and reactivity are understood. This work reports structural characterization of an interstratified illite/smectite clay, including a quartz impurity, upon heating using 27Al and 29Si MAS NMR spectroscopy and ICP-OES analysis. During dehydroxylation (600–900°C) the Q3-type SiO4 sites become disordered and octahedral AlO6 sites transform into tetrahedral sites, resulting in an amorphous material with substantial pozzolanic properties, as demonstrated by reactivity tests and hydration studies of a Portland cement–calcined clay blend. At higher temperatures (above 950°C), inert Q4-type phases crystallize which radically reduce the reactivity. At optimum calcination temperature (900°C), the amorphous material contains highly dissolvable elemental species as seen from complementary ICP-OES analysis. The quartz impurity exhibits a unique variation in 29Si spin–lattice relaxation times upon heat-treatment which is ascribed to changes in the concentration of impurity ions in quartz.