An intelligent pillbox with volume detection includes an open-close structure, a first structure, an air pressure sensing module and a processor. The first structure is movably configured on the open-close structure, and moves in and out of the containing space of the open-close structure to generate a constant volume difference. The air pressure sensing module is configured in the containing space for measuring the multiple air pressure values in the airtight space. The intelligent pillbox with volume detection calculates the medicine volume by the constant volume differences and the air pressure change when the patient takes out the medicine from the medicine box. It not only can avoid the patient taking wrong medicine, but also can detect the number of remaining medicine and remind the patient to replenish the medicine in the medicine box.