Background <p>Praziquantel is the drug of choice for parasitic diseases such as opisthorchiasis, schistosomiasis, and taeniasis. The U.S. Food and Drug Administration and World Health Organization (WHO) advise administering praziquantel with food to increase absorption and decrease side effects. However, there is a scarcity of evidence on the impact of food, and different types of food, on treatment outcomes. This review aims to address this knowledge gap by (i) examining how pre-treatment food intake is reported in humans, and characterising the types of food provided, if any, and (ii) assessing whether the presence and/or type of food impacts four key treatment outcomes in humans: absorption, metabolism, treatment-associated side effects, and drug efficacy.</p> Methods <p>We will search the following databases: Embase (via Ovid), MEDLINE (via PubMed), Web of Science Core Collection, Cochrane Central Register of Controlled Trials (CENTRAL), and African Index Medicus (via Global Index Medicus), and trial registries including clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). Additionally, we will perform citation and grey literature searching and will contact researchers to obtain information on ongoing and unpublished relevant research. The search strategy is constructed using two core concepts: (i) praziquantel, and (ii) the outcomes of interest (pharmacokinetics, treatment-associated side effects, and drug efficacy). In Covidence, two review authors will independently screen the retrieved studies based on pre-defined inclusion/exclusion criteria and extract data using a standardised form. Risk of bias will be assessed using the Risk of Bias 2 (RoB 2) tool for randomised controlled trials and the Risk of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool for non-randomised studies. Data will be synthesised narratively, and random-effects meta-analyses will be conducted to estimate the effect of food on the outcomes of interest, where appropriate. The certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.</p> Discussion <p>This review has the potential to enhance treatment outcomes for individuals and communities living in endemic regions for schistosomiasis and other parasitic diseases treated with praziquantel. Our findings will be of direct relevance for WHO guidelines and, therefore, can help improve the design and impact of future targeted treatment and mass drug administration (MDA) programmes.</p> Systematic review registration <p>PROSPERO CRD420251024296</p>