Venous thromboembolism (VTE) in children is a rare but serious event. Current guidance on pharmacological thromboprophylaxis in children is mostly based on adult studies and expert opinions. The aim of this systematic review was to examine under which conditions children (age ≤ 18 years) would benefit from pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin. Eligible studies included children, who did not receive pharmacological thromboprophylaxis as comparator, and VTE events were radiologically verified. MEDLINE and Embase were searched up to October 3, 2021. Ten studies were included presenting data for 976 children receiving pharmacological thromboprophylaxis. We divided the studies into three categories based on the population studied: children in the intensive care unit (n = 2), children with fractures and/or undergoing surgery (n = 5), and children with systemic disease (n = 3). A lower incidence of VTE was found when pharmacological thromboprophylaxis was used compared with no prophylaxis in children in intensive care unit with central venous catheter and mechanical ventilation (7/27 vs. 13/24), children in the intensive care unit admitted after trauma with a very high risk of VTE based on several risk factors (0/21 vs. 13/96), and children with acute lymphoblastic leukemia treated with L-asparaginase concomitant with steroid and presence of central venous catheter (0/82 vs. 8/121). Pharmacological thromboprophylaxis was not associated with an increased bleeding risk. In conclusion, pharmacological thromboprophylaxis in children is sparsely investigated. Only children with several risk factors for VTE are likely to benefit from pharmacological thromboprophylaxis.