In this study, Iraqi high-calcium bentonite was used for the first time to prepare natural pozzolan for concrete by the thermal activation method (calcination). Raw bentonite was calcined at 700, 750, 800, 850, 900, and 950°C for 30, 60, 90, and 120 minutes at each temperature. X-ray diffraction and quantitative X-ray diffraction techniques identified the optimal calcination program at 800°C for 90 minutes. In this program, calcination destroyed the crystal structure of bentonite-forming clay minerals, thus converting silicon, aluminium, and iron oxides into chemically reactive amorphous phases. The prepared natural pozzolan achieves a strength activity index of 108.3% at 28 days; additionally, it meets the requirements of the Iraqi specification of pozzolanic materials. The effects of Portland cement replacement with calcined bentonite at 5, 10, 15, 20, 25, and 30% were studied on selected properties of the cementitious binder and concrete. The results indicate that replacement percentage is positively associated with initial and final setting times and negatively correlated with the concrete slump. At seven days, calcined bentonite causes the decline of the compressive strength of concrete, while at 28 days, concretes containing 5, 10, and 15% develop higher compressive strength than the control mix. However, the compressive strength of concretes containing calcined bentonite differs from the control mix by not more than ±9% at 90 days. Calcined bentonite reduces the concrete splitting strength and density properties, and the absorption at 25% substitution or less.