Stress-related comorbid illnesses such as depression, anxiety disorders, hypertension, and heart disease are responsible for considerable disability worldwide. Using a combination of psychological and physiological approaches, the intent of this study was to investigate whether practicing qigong helps to reduce stress and anxiety, thus enhancing body-mind wellbeing. A randomized controlled clinical trial was conducted. Thirty-four healthy middle-aged adults participated in an 8-week qigong program. Their outcomes were compared with 31 matched subjects in the wait list control group. The outcome measures included measures of mood states (Depression Anxiety Stress Scales-21 (DASS-21)), quality of life (ChQOL), and physiological measures of stress (salivary cortisol level and blood pressure). GLM was used to analyze the data of the two groups collected in the 1st, 4th, 8th, and 12th weeks. In week 8, the treatment group had significant reduction in cortisol level and blood pressure when compared with the control group. In week 12, the qigong group had significant positive changes in the DASS-21 scales, the ChQOL scales, cortisol level, and blood pressure when compared with the control group. In general, the qigong group enjoyed better quality of life, had more positive affect, lower cortisol levels and blood pressure than the control group. The present findings support that qigong has a positive effect on reducing stress and anxiety and enhancing body-mind well-being. In this study, we restructured a traditional qigong exercise into a systematic workout structure and demonstrated its positive impact on mood regulation as illustrated by both psychological and physiological measures.