From a BPS perspective, COPD and other chronic diseases may have a significant negative impact on those living with them and may be associated with higher rates of depression and anxiety and lower levels of health-related quality of life (HRQOL). Certain factors, such as spirituality, may influence the negative impact of chronic disease on the relationship between mood and functional independence and HRQOL. Also, gender may influence the relationship between mood, spirituality, and HRQOL for men and women living with chronic diseases. The current study included 136 patients undergoing physical rehabilitation at an IRF. Anxiety, depression, spirituality, HRQOL, and functional independence were evaluated for all. Mediation models were tested to determine the impact of spirituality on the relationships between mood and HRQOL and functional independence, and moderation models were tested to evaluate the impact of gender on the relationships between mood, spirituality, functional independence, and HRQOL. The current study yielded some inconclusive results but did evidence that COPD patients in acute inpatient physical rehabilitation facilities (IRF) have higher levels of anxiety than patients without COPD and also revealed that men with COPD have better HRQOL than do women with COPD. Spirituality was found to partially mediate the relationship between depression and HRQOL in IRF patients with COPD, but gender did not appear to moderate the relationships between mood, spirituality, functional independence, or HRQOL in IRF patients. As few studies on IRF patients with chronic diseases exist, continuing to evaluate patients in IRFs is important to enhance our BPS understanding of chronic disease.