Background: Of all central nervous systems tumors, 10–20% are located in the brainstem; diffuse intrinsic pontine glioma (DIPG) is diagnosed in 80% of them. With over five decades of clinical trial testing, there are no established therapeutic options for DIPG. This research article aims to collate recent clinical trial data and provide a landscape for the most promising therapies that have emerged in the past five years. Methods: PubMed/MEDLINE, Web of Science, Scopus, and Cochrane were systematically searched using the following keywords: Diffuse intrinsic pontine glioma, Pontine, Glioma, Treatment, Therapy, Therapeutics, curative, and/or Management. Both adult and pediatric patients with newly diagnosed or progressive DIPG were considered in the clinical trial setting. The risk of bias was assessed using the ROBINS-I tool. Results: A total of 22 trials were included reporting the efficacy and safety outcomes among patients. First, five trials reported outcomes of blood–brain barrier bypass via single or repeated-dose intra-arterial therapy or convection-enhanced delivery. Second, external beam radiation regimens were assessed for safety and efficacy in three trials. Third, four trials administered intravenous treatment without using chemotherapeutic regimens. Fourth, eight trials reported the combinations of one or more chemotherapeutic agents. Fifth, immunotherapy was reported in two trials in an adjuvant monotherapy in the post-radiotherapy setting. Conclusion: This research article captures a clinical picture of the last five years of the direction toward which DIPG research is heading. The article finds that re-irradiation may prolong survival in patients with progressive DIPG; it also instills that insofar palliative radiotherapy has been a key prognostic choice.