Schistosomiasis is associated with a lot of morbidity and mortality. Although the World Health Organization (WHO) recommends that a single dose of praziquantel (PZQ) administered annually can reduce morbidity for a year, other reports show that it can reduce and maintain low morbidity levels up to two years. However, there is a paucity of data on the evaluation of the effects of these two treatment regimens on morbidity control. Therefore, this was a retrospective cohort study evaluating the effects of the two treatment regimens on Schistosoma mansoni morbidity over a period of two years along the shores of Lake Victoria. A total of 398 pupils from 12 schools were enrolled and randomized into arm 1 where children received two doses of PZQ and arm 2 who received a single dose in two years. The children were examined for S. mansoni infection, malaria parasites, hemoglobin levels and liver and spleen morbidity using the Kato-Katz method, microscopy, Hemocue machines and abdominal ultrasound respectively. Data was analyzed using paired and unpaired t test, partial correlation to test for associations while chi-square test was used to test for proportionality. The results show that although S. mansoni prevalence and infection intensity declined in both arms of treatment, the differences were not statistically significant. However, there was a significant increase in malaria prevalence at follow up in both treatment arms (Arm 1, P = 0.002; arm 2, P < 0.001). Moreover, all the morbidities increased post-treatment with significant differences in liver pattern 2: B (Arm 1, P < 0.001; Arm 2, P = 0.025) and anaemia (p < 0.001 in both arms). Further analysis revealed that S. mansoni was negatively correlated with splenomegaly before treatment in both arms of treatment (Arm 1, r = -0.392, P = 0.001; Arm 2, r = -0.443, P = 0.001, respectively) while at follow up it was negatively correlated with liver pathology (r = -0.182, P = 0.007) and hepatomegaly (r = - 0.147, P = 0.030) in arm 1 schools. In addition, malaria was positively correlated with splenomegaly pre-treatment (r = 0.160, P = 0.018) and hepatomegaly (r = 0.160; P = 0.018) and liver pattern 2: B (r = 0.177; P = 0.023) post-treatment. A common occurrence pattern in S. mansoni infection and associated morbidities was observed in the two treatment arms at follow up indicating that no treatment arm was superior to the other one. In addition, the increase in all morbidities post-treatment was an indication that morbidity in this region may be influenced by other co-infections. Knowledge obtained from this study will be applied in policy-making by Ministry of Health to improve on the existing intervention strategies for the control of schistosomiasis morbidity.