Background: Living with hand eczema (HE) has been associated with impaired quality of life (QoL), having anxiety and depression but the magnitude of association is not clear. Objectives: The aim of this systematic review and meta-analysis was to determine the psychological burden in terms of anxiety, depression and quality of life in patients with HE. Methods: Several databases were systematically searched. Weighted means with standard deviation (SD) were calculated for disease severity, QoL, depression and/or anxiety scores among patients with HE. For studies presenting QoL, depression and/or anxiety scores in patients with HE and in controls the weighted means were compared with an unpaired t-test. In studies reporting Hand Eczema Severity Index (HECSI) and Dermatology Life Quality Index (DLQI), the correlation between HECSI and DLQI was estimated using Spearman's rank correlation (rs). Results: In total, 81 studies encompassing 17,835 patients with HE and 31,541 controls were included. The weighted mean DLQI was 10.66 (SD 8.93) corresponding to a moderate-to-large effect on QoL and a strong correlation (r_s: 0.76, 95% CI:0.56–0.87) between DLQI and HECSI was observed. The mean EQ-5D-VAS was significantly lower in patients with HE compared with controls (68.03 (SD 10.52) vs. 80.63 (SD 1.17), p < 0.00001). Patients with HE had higher mean HADS (Hospital Anxiety and Depression Scale) anxiety score (7.4 vs. 5.8, p = 0.0008) than controls but not higher HADS depression score (6.5 vs. 5.7, p = 0.32). Only one study assessed risk of anxiety, depression and suicidal ideation showing an increased odds of all diseases among patients with HE compared with controls. Conclusion: Hand eczema has a moderate-to-severe impact on quality of life with a strong correlation between disease severity and impact on quality of life. Patients with hand eczema have an impact on QoL comparable to other chronic diseases when measured with generic QoL scoring systems.