Reperfusion therapies have become the standard of care for patients with acute ischemic stroke (AIS). However, around half of treated patients do not regain functional independence despite successful recanalization. Potentially avoidable unbalanced states that prevail both before and after reperfusion therapy might account for such unfavorable functional outcomes. They include energy supply versus energy demand in the ischemia phase, hypoperfusion versus hyperperfusion in the reperfusion phase, and acute cytotoxic versus prorepair inflammation in subacute and chronic stages. Classical pharmacological approaches only target one of these imbalances, which is insufficient. Nonpharmacological therapies are typically multitargets and have provided new evidence for benefit in AIS. This topical review discusses the latest evidence regarding nonpharmacological strategies for brain cytoprotection in AIS targeting the 3 above imbalances. We also focus on the mechanisms underlying the benefits of nonpharmacological therapies and present promising results from recent large-scale clinical trials testing them in AIS. We further elaborate on the prospects of several nonpharmacological brain protection strategies applied in the different AIS scenarios. By gaining a deeper understanding of the imbalanced states in AIS and the advantages of nonpharmacological brain cytoprotection therapies, future clinical trials may be further refined to translate nonpharmacological brain cytoprotection therapies to the clinic.