AIMS: Fracture-related infections (FRIs) are a major concern for patients and healthcare systems, yet their impact on mental health has been largely overlooked. This study aimed to assess the longitudinal impact of FRI on patients' quality of life. METHODS: A prospective study was conducted at a level 1 trauma centre between January 2020 and December 2022. In total, 56 patients participated, with quality of life assessed at five timepoints: one week preoperatively, and one, three, six, and 12 months postoperatively. Statistical analysis was performed using repeated measures analysis of variance (ANOVA) with adjusted post-hoc analysis. RESULTS: The preoperative Physical Component Summary score on the 36-Item Short-Form Health Survey questionnaire (SF-36) was 26.71, increasing to 30.40 at one month, remaining stable at three months. A modest increase was observed at six months (32.45, p = 0.003), but it decreased to 29.72 at 12 months. The preoperative Mental Component Summary score (SF-36) was 46.48, decreasing to 39.89 at one month (p = 0.027) and to 36.03 at three months (p ≤ 0.001). However, it improved at six (42.74) and 12 months (44.05). Positive changes were seen in EuroQol five-dimension questionnaire (EQ-5D) subdimensions, such as mobility, self-care, usual activities, and pain/discomfort, while anxiety/depression scores decreased over time. The EQ-5D visual analogue scale (VAS) score increased to 62.79 at six months (p ≤ 0.001) and decreased to 58.2 at 12 months (p = 0.011). CONCLUSION: FRIs substantially affect mental health and quality of life, particularly during the initial three months of treatment. This study emphasizes the importance of addressing psychological aspects early in FRI management, advocating for holistic care encompassing both physical and psychological aspects of treatment.