This study aimed to analyze the factors of rapid attenuation of graft endothelium in the early stage after penetrating keratoplasty (PKP), with a view to guiding patients with PKP to better long-term outcomes. This study included 226 patients who underwent PKP with follow-up time >1 year at the Qingdao Eye Hospital of Shandong First Medical University from January 2018 to June 2020. Medical records were retrospectively studied, and donor factors, patient factors, and surgical factors were comparatively analyzed to clarify those affecting the rapid decay of graft endothelium after PKP. The median time between excision and death >60 min and patient age >60 years were risk factors for endothelial cell loss (ECL) rate >30% at 1 month postoperatively. However, a higher percentage of patients with donor age ≤60 years and Optisol preservation solution had endothelial cell density (ECD) >2000 cells/mm2 in the graft at postoperative 1 year. A year after the surgery, patients with corneal endothelial decompensation and immune rejection were at risk for ECD < 1000 cells/mm2. The combined operations had a significant effect on the ECL in the early postoperative period. Patients who underwent combined extracapsular cataract extraction or intraocular lens implantation had a significantly higher rate of ECL at postoperative 1 month than other patients, and no significant effect at postoperative 1 year. However, patients without combined operations have a higher probability of maintaining a high level of graft ECD. The graft diameter also affected postoperative ECL. In patients with a larger graft diameter, attenuation of ECD was slower. The ultimate goal of PKP is to maintain graft transparency for extended periods. The use of younger donors, minimizing unnecessary operation in the anterior chamber, and minimizing immune rejection may maintain a greater donor corneal endothelium in the long term.