Optical neuroimaging with functional near-infrared spectroscopy (fNIRS) enables the quantification of changes in cerebrovascular hemodynamics and oxygenation associated with neuronal activity. This chapter summarizes a recently published fNIRS study by the authors, which investigated the acute neurovascular and systemic physiological effects of a subanesthetic ketamine dose in humans (Castillo et al.). In this single-blind, placebo-controlled fNIRS study with a nonrandomized design, we employed a novel time-domain near-infrared spectroscopy system, Kernel Flow1, to assess the acute changes in cerebrovascular correlates of brain activity following intramuscular subanesthetic ketamine administration. Additionally, the study included the measurement of changes in systemic physiological activity. Fifteen healthy participants (8 females, 7 males; age 32.4 ± 7.5 years) received either 0.75 mg/kg ketamine or a placebo (saline) in a clinical setting. The administration of ketamine was found to result in the following acute effects: (i) altered states of consciousness, (ii) a reduction in the fractional amplitude of low-frequency fluctuations across the entire brain, (iii) a decrease in the global brain connectivity of the prefrontal region, and (iv) changes in systemic physiology (e.g., increase in pulse rate and electrodermal activity, decrease in pulse rate variability). Furthermore, we found that a combination of fNIRS-based brain activity and systemic physiological metrics could serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Our study is the first fNIRS study to examine the effects of ketamine in humans. It demonstrates the great potential of fNIRS for investigating the neurovascular effects of ketamine in particular and psychedelics in general.