A method for controlling a histotripsy using a confocal fundamental and harmonic superposition combined with hundred-microsecond ultrasound pulses, including: 1) positioning a target tissue by a monitoring and guiding system and adjusting a position of the target tissue to a focal point of a transducer; 2) first stage: controlling the confocal fundamental and harmonic superposition combined with hundred-microsecond ultrasound pulses to form a shock wave in a focal zone; wherein a negative acoustic pressure exceeds a cavitation threshold; an inertial cavitation occurs to generate boiling bubbles; the boiling bubbles collapse and achieve partial homogenization of the target tissue; 3) second stage: controlling the confocal fundamental and harmonic superposition combined with hundred-microsecond pulsed-ultrasound sequences to simultaneously irradiate a target zone and further mechanically disintegrate and homogenize the target tissue.