Clostridium perfringens (C. perfringens) is one of the most common pathogens affecting sheep, causing significant economic losses due to high mortality rates. The aim of this study is to isolate and identify C. perfringens from lambs that had recently died from enterotoxemia and study the histopathological changes in their intestines, livers and kidneys. A total of forty-eight samples (16 swabs from each of the intestines, liver, and kidneys) were collected from the lambs. All the collected swabs from the internal cavity of the small intestine, liver or kidney were placed in sterile tubes prepared with thioglycolate broth. Tissue samples were also taken from the intestine, liver and kidney and placed in 10% formalin (NBF) containers. The samples were transferred to the scientific research unit at the College of Veterinary Medicine, Hama University for bacteriological and histological testing. All swabs underwent bacteriological examinations by both conventional and molecular techniques for the detection of C. perfringens. The cpa, cpb, etx, and ia genes were also investigated. The total isolation percentage was 79.16%, and the highest isolation percentage was recorded in intestine followed by liver and kidneys at 33.33%, 22.92%, and 22.92%, respectively. The study also revealed the presence of cpa, cpb, etx and ia genes at rates of 44.73%, 21.05%, 34.21%, and 5.26% among isolates. The results of the histopathological examination revealed that all the intestinal sections, liver and kidneys had various pathological lesions. This study provides an opportunity to know the pathogenic types in lambs that died as a result of C. perfringens infection and could serve as a useful control element for the development of vaccines to reduce and control this economic loss in lambs.