Abstract: Background: Chemotherapy-induced cognitive impairment, also known as “chemobrain,” is a common side e?ect. Over the past five years, we have conducted a series of studies to explore its pathophysiological mechanisms and the effects of the two natural compounds, resveratrol and ginsenoside Rg1, in preventing chemobrain in animal models. We also have completed a clinical trial evaluating the efficacy of acupuncture prevention of chemobrain in breast cancer patients undergoing chemotherapy. Methods: for animal studies, a mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Resveratrol or Rg1 was given one week prior to DAC regimen for three weeks. Behavioral paradigms, in vivo neuroimaging, cytokine and molecular examinations were used to detect the effects of DAC and natural compounds. In a randomised controlled trial, 60 breast cancer patients who were undergoing chemotherapy were randomly assigned to comprehensive acupuncture treatment (CAT, n = 30) and control treatment with least acupuncture stimulation (LAS, n = 30) for 2 sessions per week for 8 weeks. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) at baseline and once biweekly thereafter. Results: (1) Animal model: Cotreatment with both natural compounds significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that natural compounds reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. They normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Resveratrol and Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. They also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. (2) Clinical trial: CAT-treated patients had significantly or marginal significantly greater improvement on total score on MoCA, score on attention and delayed recall subscale than LAS group at multiple assessment points. Conclusions: Resveratrol and Rg1 exert their anti-chemobrain effects in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing. Acupuncture therapy may be an effective intervention in preventing and ameliorating chemobrain