Background/Objectives: Furan derivatives are commonly encountered in food and environmental matrices and may exert biological effects, but their acute cardiovascular actions and potential mitochondrial targets remain insufficiently characterised. This study examined the effects of two simple furan compounds, 2-acetylfuran (2AF) and 5-methylfurfural (5MFF), on arterial blood pressure in vivo and on oxidative phosphorylation in isolated rat liver mitochondria. Methods: Arterial blood pressure was recorded invasively in anaesthetised rats after intraperitoneal administration of 2AF or 5MFF (0.3 µL/g). Systolic, diastolic, and mean arterial pressures, as well as heart rate, were monitored over time. Mitochondrial respiration was assessed in isolated rat liver mitochondria using high-resolution respirometry. Results: Both 2AF and 5MFF induced a rapid hypotensive response, with significant reductions in systolic, diastolic, and mean arterial pressures within 10–15 min after administration. MAP was reduced to a similar extent by both compounds. However, their chronotropic and pulse pressure responses differed: 5MFF increased heart rate and pulse pressure, whereas 2AF induced a delayed bradycardic response without a significant change in pulse pressure. In isolated liver mitochondria, both compounds markedly reduced ADP-stimulated respiration and decreased the respiratory control index, indicating reduced coupling efficiency. Both compounds also increased the cytochrome c effect, suggesting partial impairment of outer mitochondrial membrane integrity. Conclusions: 2AF and 5MFF exert acute hypotensive effects in anaesthetised rats and impair oxidative phosphorylation in isolated rat liver mitochondria. This study provides the first in vivo evidence that 2AF and 5MFF exert hypotensive effects and identifies them as bioactive furan compounds with dual haemodynamic and bioenergetic actions.