Mild traumatic brain injury (mTBI) is a global public health problem and its current management is limited to rest and symptom management. Despite frequent use of drugs for symptom control, there is a lack of consensus on the optimal pharmacological management of post-concussive symptoms. We reviewed the relevant literature to compile the evidence about the pharmaceutical management of pediatric mTBI. We performed a systematic review of the literature available in PubMed, Cochrane CENTRAL, and ClinicalTrials.Gov as well as through citation tracing. A modified PICO framework was used for the construction of search strategy and eligibility criteria. Risk of bias was assessed using RoB-2 tool for randomized and ROBINS-I for non-randomized studies. A total of 6260 articles were screened for eligibility. After exclusions, a total of 88 articles received full text review. A total of 15 reports representing 13 studies (5 randomized clinical trials, 1 prospective randomized cohort study, 1 prospective cohort study, and 6 retrospective cohort studies) met the eligibility criteria and were included in the review. We identified 16 pharmacological interventions in a total of 931 pediatric patients with mTBI. Amytriptiline (n = 4), ondansetron (n = 3), melatonin (n = 3), metoclopramide (n = 2), magnesium (n = 2), and topiramate (n = 2) were investigated in multiple studies. All RCTs were relatively of small size (n ≤ 33/group). The available evidence supporting pharmacological intervention in pediatric mild traumatic brain injury is scarce. We propose a framework to facilitate future collaborative research efforts to test and validate various pharmacological interventions for acute and persistent post-concussive symptoms in children.