Background: Vascular brachytherapy (VBT) used to be an effective treatment modality for management of in-stent stenosis but was superceded by drug eluting stents (DES) which had shown a greater efficacy. However, there is no clear evidence to support superior management for in-stent restenosis (ISR) which continues to be a challenge. Methods: We conducted a systematic review of the literature and appraised PubMed, Medline, Web of science, ProQuest and Cochrane databases from 2000 to 2020. We assessed comparative outcomes including efficacy (as assessed by measuring major adverse cardiac events, target vessel revascularisation, target lesion revascularisation, all-cause mortality, target lesion myocardial infarction and stent thrombosis) and safety of VBT. Results: Of 1083 records obtained, a total of 8 retrospective studies met the inclusion criteria. In the included studies, major adverse cardiac events (MACE) rates ranged from 10% to 17.5% in the VBT group compared to 14.1% to 28.2% in the re-DES group at one year follow up. There were lower rates of target vessel revascularisation (VBT 10–22.8%; control 18–22.9%) and target lesion revascularisation (VBT 10–14.1%, Control 8–22.1%) between the VBT and re-DES groups. There were significantly low rates of all-cause mortality (1–5.4%), target lesion myocardial infarction (0–7%) and stent thrombosis (0–2.1%) in the VBT group at one year. Conclusions: VBT is considered to be an effective and safe treatment strategy in complex patients with multiple risk factors for DES-ISR in initial reports. There are no long-term comparison studies available beyond 1 year. There is a need for randomised controlled trials to objectively assess the role of VBT compared to DES and drug coated balloons.