<p>Nursing students face high academic and emotional demands that may adversely affect their mental well-being and psychological resources. Understanding the relationships between stress, life orientation, and sense of coherence is essential for developing effective support strategies. This study aimed to examine the mediating role of perceived stress in the relationship between life orientation and sense of coherence among nursing students, with the year of study as a moderator. A multicentre cross-sectional study was conducted between October and December 2023 among 2,689 undergraduate nursing students in Poland aged 18–30 years. Data were collected using a sociodemographic questionnaire and standardized instruments: LOT-R, SOC-29, and PSS-10. Moderated mediation analyses were performed. Most participants reported high levels of perceived stress and high dispositional optimism, while sense of coherence scores were moderate. Optimism showed a negative direct association with meaningfulness, which strengthened in the second year of study and became partially mediated by stress in the third year. In the first two years, higher optimism was associated with lower manageability; this relationship weakened in the third year, suggesting adaptive changes. The third year emerged as a critical period, during which stress significantly reduced comprehensibility and meaningfulness and played a stronger mediating role between optimism and sense of coherence. Perceived stress mediates the relationship between life orientation and sense of coherence in nursing students, with patterns differing across years of study. These findings highlight the need for targeted educational and psychological interventions to enhance stress management, emotional resilience, and psychological resources, particularly in later stages of nursing education.</p>