Purpose <p>To explore the trajectories of shoulder-related quality of life (QoL) in patients with head and neck cancer undergoing neck dissection, identify factors associated with each trajectory, and determine whether shoulder function differs across different trajectories.</p> Methods <p>Patients with head and neck cancer who underwent neck dissection were followed up at 3 days, 2 weeks, 1 month and 3 months after surgery. A sociodemographic information questionnaire, the Neck Dissection Impairment Index, and the Constant-Murley score were completed. A latent class growth analysis was used to explore the trajectories of shoulder-related QoL.</p> Results <p>The average age of the 92 patients with head and neck cancer who underwent neck dissection was 37.68 years. The majority of participants had thyroid cancer (88.0%). Two distinct shoulder-related QoL trajectories were identified: 45 patients (48.9%) in the “Persistently High QoL” group (trajectory 1) and 47 patients (51.1%) in the “Low QoL with Gradual Improvement” group (trajectory 2). When trajectory 1 was used as the reference, the predictors for trajectory 2 included irregular exercise and receiving Level V regional dissection. The Constant-Murley scores were consistently higher in the “Persistently High QoL” group than in the “Low QoL with Gradual Improvement” group, with statistically significant differences observed at postoperative day 3 (<i>t</i> = 3.979, <i>P</i> &lt; 0.001), week 2 (<i>t</i> = 4.420, <i>P</i> &lt; 0.001), and month 1 (<i>t</i> = 3.436, <i>P</i> = 0.001).</p> Conclusion <p>We identified two trajectories of shoulder-related QoL. Dynamic and individualized exercise rehabilitation interventions should be continuously provided to ensure that patients recover better shoulder function and improve their shoulder-related QoL.</p>