Provided is a substrate processing apparatus and a method of manufacturing a semiconductor device, which are hard to cause a defect in processing a substrate owing to that a pressure inside a process chamber is not kept constant, and which enable a better processing of a substrate. The substrate processing apparatus has: a process chamber for processing a substrate; a reactive gas-supplying module for supplying a reactive gas into the process chamber; a reactive gas-supplying line for supplying the reactive gas from the reactive gas-supplying module into the process chamber; an exhaust line for exhausting an inside of the process chamber; a pump provided in the exhaust line for vacuumizing the inside of the process chamber; a pressure-adjusting valve provided in the exhaust line for adjusting a pressure in the process chamber; a first pressure-measuring instrument for measuring an inside pressure of the process chamber; a second pressure-measuring instrument for measuring a differential pressure between the inside pressure of the process chamber and an outside pressure thereof; and a controller which controls the pressure-adjusting valve based on a value of the inside pressure of the process chamber measured by the first pressure-measuring instrument so as to keep the inside pressure of the process chamber constant, and controls the reactive gas-supplying module based on a value of the differential pressure measured by the second pressure-measuring instrument so as to allow supply of the reactive gas into the process chamber in a case of the inside pressure of the process chamber being smaller than the outside pressure thereof, and so as to preclude supply of the reactive gas into the process chamber in a case of the inside pressure of the process chamber being larger than the outside pressure thereof when processing the substrate.