Aim. This study aims to identify the factors that influence humanistic practice ability, validate the relationship among social support, empathy, self-efficacy, and humanistic practice, and provide reference basis for developing intervention measures. Background. Cultivating humanistic practice ability in clinical nurses is essential for improving the quality of nursing care. Methods. From February to March 2022, a cross-sectional survey was conducted in top three hospitals in central China. The study used a self-designed questionnaire to ascertain the general characteristics of the participants. The Nurses’ Humanistic Practice Ability Scale, Jefferson Empathy Scale, Perceived Social Support Scale, and General Self-Efficacy Scale were used. Data were analyzed using Spearman’s correlation and a structural equation model through statistical product and service solutions (SPSS) and analysis of moment structure (AMOS). Results. A total of 650 clinical nurses were included in this study. The average age was 32.35 ± 8.35 years. The Nurses’ Humanistic Practice ability Scales score was 107.49 ± 19.32. Nurses’ humanistic practice ability showed a positive correlation with social support (r = 0.455), self-efficacy (r = 0.369), and empathy (r = 0.375) (all
p
< 0.001). Empathy totally mediated the relationship between social support and humanistic practice ability. In addition, self-efficacy and empathy served as sequential mediators in the association. Conclusion. Social support can influence the humanistic practice ability through self-efficacy. In addition, the higher the level of social support, the higher the level of self-efficacy, which further promotes the improvement of their empathy and eventually leads to stronger humanistic practice ability. Therefore, the corresponding measures to promote the humanistic practice ability of nurses can be formulated from the abovementioned three aspects. Implications for Nursing Management. We recommend that hospital administrators provide nurses with more comprehensive social support and develop intervention strategies to enhance nurses’ self-efficacy and empathy, which help to improve the nurse’s humanistic practice ability.