Natural spices have gained much attention for their aromatic and pungent flavors as well as their multiple beneficial health effects. As complex organelles that play a central role in energy production, stress response control, cell signal transduction, and metabolism regulation, mitochondria could be regulated by many bioactive components in spices. In this review, the role of mitochondria in maintaining cellular and metabolism homeostasis is summarized. The regulatory effects of mitochondrial function by major bioactive compounds from natural spices are evaluated, including capsaicin, 6-gingerol, 6-shogaol, allicin, quercetin, curcumin, tetrahydrocurcumin, and cinnamaldehyde. The underlying molecular mechanisms are also discussed. This work could enhance our understanding toward health-promoting properties of spice compounds as well as provide new insights into the prevention and treatment of disorders associated with mitochondrial dysfunctions by those nutraceuticals.