An infant safety seat with an adjustable accommodating space includes a multi-layer cushioning insert which is detachably insertable into an infant safety seat for accommodating an infant in different stages of growth with different sizes. The multi-layer cushioning insert comprises a first cushioning part and a second cushioning part both may detachably to overlap each other and connect into the accommodating space to provide the necessary support for keeping an infant in proper postural position. The first cushioning part includes a U-shaped head cushion part, U-shaped body cushion part and U-shaped leg cushion part for restricting the side moving of the infant. Further, for accommodating a smaller infant, the second cushioning part can be detachably overlapped onto the first cushioning part for further reducing the side moving space and upright moving space of the baby in the infant safety seat.