Elders with chronic medical conditions are vulnerable to depression. Mainstream interventions for treating their depression is however far from satisfactory which stimulates the interests of researchers to look for alternative therapies to alleviate geriatric depression. Qigong, a Chinese mindful exercise, is demonstrated to have anti-depressive effects. Results of our earlier studies shed light on the psychological mechanism underlying this effect. The neurobiological mechanism remains unclear. This article attempts to review extant evidence and suggests possible neurobiological pathways of the anti-depressive effect of qigong based on the neurotransmitter, neuroendocrine, and neurotropic perspectives. Further research to consolidate its scientific base is suggested.