With the growing incidence of closed schistosomiasis and uncommon presentations, there is a risk of the infection rate being underestimated. A study in Japan reported an unexplained case of endocarditis that was finally diagnosed as a complex Schistosoma japonicum infection; in the absence of advanced techniques, the diagnosis was delayed. We therefore set out to explore the incidence of Schistosoma mansoni in endocarditis patients coming from areas of Egypt where S. mansoni is endemic. We also investigated histopathological changes in the cardiac valves and the presence of cell-free parasite DNA (CFPD) in cardiac tissues of laboratory mice infected with S. mansoni. The study included 186 patients with the manifestations of infective endocarditis. Eggs were detected in the stool samples of 5.91% of patients. Seropositivity was reported in 23.66% of patients and antigen was detected in the urine samples of 10.21%. Using real-time polymerase chain reaction (PCR), CFPD was detected in the blood of 6.98% of the endocarditis patients and 95% of the infected mice, while the cardiac samples of 45% of the mice tested positive for CFPD (means ± SD = 1390.2 ± 283.65, 2158.72 ± 1103.1 and 5.71 ± 2.91, respectively). Histopathological examination revealed abnormal collagen deposition, inflammatory cells and haemorrhagic pigmentation in the heart sections. Despite the low incidence of S. mansoni infection in the studied cohort, the presence of CFPD in the cardiac tissue of infected mice makes it necessary to: (1) investigate the hazards of CFPD deposition in endothelium-rich organs; and (2) test the potential of CFPD to trigger tissue inflammation, abnormal proliferation or genome integration.