Intravenous recombinant tissue-type plasminogen activator (r-tPA, alteplase) remains the recommended therapy for acute ischemic stroke. However, several factors are limiting its practical use. It makes it urgent for us to search more efficient strategies that can save the ischemic neurons, and safely extend the time window, while in the mean time reducing the detrimental effects for stroke thrombolysis. Hyperbaric oxygen therapy (HBOT) is considered to be potentially neuroprotective. Co-administration of r-tPA and HBOT has already been proved to be effective, safe and feasible in myocardial infarction. In this article, we would like to review whether HBOT has any beneficial effects on r-tPA thrombolysis. If there is, what is the underlying possible mechanisms and how to optimize for maximal effects?