Thermal therapies have strong potential for improving outcomes for patients suffering from cardiac arrest, neonatal hypoxic-ischemic encephalopathy, or medically refractory intracranial hypertension. We propose a novel tool to manipulate blood temperature through extravascular thermoelectric heat exchange of blood vessel walls and flowing blood. This tool is a concentrated cooling probe with several thermoelectric units combined to focus cooling at the application site. Using this tool, we aim to achieve desired levels of temperature control and potentially reduce complications associated with traditional intravascular or systemic thermal therapies. Leveraging the feedback control, speed, and reversible operation of thermoelectric cooling modules, the device can adapt to cool or heat as desired. Preclinical testing on rodent models confirmed rapid, significant reduction of intravenous jugular blood temperature when a prototype device was brought in contact with the left carotid artery (change in blood temperature of −4.74 ± 2.9 °C/h and −4.29 ± 1.64 °C/h for 0 °C and −5 °C cooling trials, respectively). Declines in rectal temperature were also noted, but at lesser magnitudes than for jugular blood (0 °C: −3.09 ± 1.29 °C/h; −5 °C: −2.04 ± 1.08 °C/h), indicating proof-of-concept of thermoelectric extravascular blood cooling within a relatively localized region of the body. With further improvements in the technique, there is potential for selective organ cooling via a reduction in the temperature of flowing blood.