BACKGROUND AND OBJECTIVES: Burnout is considered a public health crisis among physicians and is related to poor quality of life, increased medical errors, and lower patient satisfaction. A recent literature review and conceptual model suggest that awareness of life meaning, or meaning salience, is related to improved stress and coping, and may also reduce experience of burnout. This study examined associations among meaning salience, burnout, fatigue, and quality of life among family medicine residency program directors. METHODS: Data were collected via an online survey administered by the Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA; n=268, response rate of 45.4%) in December 2018. Program directors completed measures of meaning salience, burnout, fatigue, and quality of life. Data were analyzed using Spearman correlations and path analysis. RESULTS: Program directors who reported greater experienced meaning salience also reported significantly less burnout (beta=-.40, P<.001) and less fatigue (beta=-.38, P<.001), which were then both significantly associated with greater quality of life (Ps<.001). Program directors who reported greater meaning salience also reported greater quality of life (beta=.21, P<.001). Additionally, there were significant indirect associations between meaning salience and quality of life through less burnout and fatigue (beta=.26, P<.001). CONCLUSIONS: The potential for increasing physicians' awareness of their sense of meaning as a means to prevent or decrease burnout is underresearched and warrants further study. Both preventive measures (eg, wellness curricula) and interventions with already-distressed physicians may encourage regular reflection on meaning in life, especially during busy workdays.