An acoustic access disconnect detection system is useful for detecting when an access needle has become dislodged or when blood is leaking. The acoustic disconnect detection system includes an acoustic transmitter and one or more acoustic sensors placed upstream of an access site of a patient, the sensors suitable for generating and detecting an acoustic signal that is intended to pass unobstructed through the access site. The acoustic transmitter may be placed on a therapy machine for generating an acoustic signal. The acoustic sensor is mounted downstream of the transmitter, such as on the therapy machine where blood is pumped to or returned from the patient, on the patient, or on the therapy machine where blood is entering the therapy machine. The therapy machine, such as a dialysis machine, may be programmed not to start or continue operation unless the acoustic signal is within certain parameters.