Endoscopic closure has become the first choice for closing iatrogenic perforations. Previously, we reported a self-developed endoscopic multifiring clip applicator (EMFCA) system. In this paper, a new EMFCA system for endoscopic closure of large perforations with a redesigned clip, the less traumatic grasper, and a highly efficient driving system was presented, and its efficacy was evaluated. The behaviors of the new clip and grasper were verified through finite element analysis (FEA). The capability of pushing transmission for the EMFCA system was identified by the proposed model and the validation experiment. Ex-vivo studies were conducted on porcine stomachs to compare the outcomes of the closures. The FEA results showed that the deformation of the clip was safe and smoother, with a maximum stress of 640.0 MPa. The less traumatic grasper could increase the grasping force and avoid trauma by exerting uniform stress along the axis. The capability of pushing transmission was enhanced by the double-nested tendon-sheath actuation system with an efficiency of 0.45–0.48. The mechanical strength, the leakage pressure, and the operating time for the closures with the new EMFCA system and the previous EMFCA system were 6.1 N ± 0.8 N, 37.1 mmHg ± 6.8 mmHg, 7.3 min ± 0.4 min and 5.1 N ± 1.0 N, 27.4 mmHg ± 6.4 mmHg, 11.4 min ±0.8 min, respectively. The new EMFCA system can realize a superior, reliable, and high-efficiency endoscopic closure of large perforations.