Background: Nontraumatic brain injury encompasses various pathological processes and medical conditions that result in brain dysfunction and neurological impairment without direct physical trauma. The study aimed to assess the efficacy of intravenous administration of 20% mannitol and 3% hypertonic saline to reduce intracranial pressure in nontraumatic brain injury. Materials and methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed for study selection and data extraction. The search was conducted in the PubMed, Embase, and Scopus databases, including articles published in English from January 2003 to December 2023. Our study included randomized controlled trials, comparative studies, prospective analyses, and retrospective cohort studies. We extracted data on baseline characteristics of patients, intervention details, major outcomes, and complications. Quality assessment was performed using the Jadad scale and the Robvis assessment tool for risk of bias. Results: A total of 14 studies involving 1,536 patients were included in the analysis. Seven studies reported hypertonic saline as more effective in reducing intracranial pressure, while three studies found similar effectiveness for both interventions. Adverse events were reported in only three studies. The studies that reported complication rates ranged from 21 to 79%. A meta-analysis was conducted on five studies, showing varying rates of adverse events associated with mannitol and hypertonic saline. Conclusion: Both hypertonic saline solution and mannitol have been explored as treatment options for decreasing intracranial pressure in nontraumatic brain injuries. While some studies indicate the superiority of hypertonic saline, others report similar effectiveness between the two interventions.