Background <p>Clinical nurses’ well-being is crucial for enhancing their performance and the quality of patient care. Understanding the factors influencing nurses’ happiness, including professional autonomy, is essential in addressing workplace stress and dissatisfaction.</p> Aims <p>This study aims to investigate the relationship between happiness and professional autonomy among clinical nurses, providing insights that can help improve job satisfaction and patient care.</p> Methods <p>An analytical cross-sectional study was conducted in Ardabil, Iran, involving 270 nurses selected through stratified sampling from May to December 2022. Data were collected using the Oxford Happiness Questionnaire and the Dempster Professional Autonomy Scale. Statistical analysis was performed using SPSS.</p> Results <p>The mean happiness score was 65.62 (SD = 14.11), with 70% of nurses reporting acceptable to high happiness levels. The mean professional autonomy score was 94.72 (SD = 13.17). A significant positive correlation was found between happiness and professional autonomy (<i>r</i> = 0.67, <i>p</i> &lt; 0.001). Work experience and income satisfaction were also associated with higher happiness levels.</p> Conclusions <p>The findings indicate that enhancing professional autonomy can increase nurses’ happiness. Creating supportive work environments that promote autonomy is essential for improving nurse well-being and the overall quality of healthcare delivery.</p>