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Abstract Background Hyperbaric oxygen therapy (HBOT) for the treatment of acute stroke has been under the radar for a long time. Previous studies have not been able to prove efficacy. Several factors might have contributed to such inconsistent results. The timing of delivering the hyperbaric oxygen in relation to the stage of stroke evolution may be an important factor. This was not taken into account in the previous studies as there was no feasible and standardized method to assess the penumbra in the acute phase. Now with the perfusion scan appearing as a key player in the acute stroke management, precise stroke patient selection for hyperbaric oxygen therapy deserves a second chance similar to mechanical thrombectomy. Case presentation A 62-year-old female patient who presented with acute large vessel stroke was not eligible for chemical or mechanical thrombectomy. There was a large penumbra on imaging. She got treated with several sessions of hyperbaric oxygen over a 2-week period immediately after stroke. The patient showed significant improvement on the follow-up perfusion imaging as well as some clinical improvement. The more impressive radiological improvement was probably due to the presence of relatively large core infarction at baseline affecting functional brain areas. The patient continued to improve clinically on her 6-month follow up visit. Conclusion Our case demonstrates immediate stroke-related penumbra improvement associated with HBOT. Based on that, we anticipate a potential role for HBOT in acute stroke management considering precise patient selection. Future randomized controlled trials are needed and should take that in consideration.