Background Depression and anxiety are common psychiatric manifestations in childhood-onset systemic lupus erythematosus (cSLE). This study aimed to determine the prevalence of clinically significant depression and anxiety, identify associated factors, and assess their impact on health-related quality of life (HRQOL) and family in patients with cSLE. Methods We conducted a cross-sectional study of cSLE patients, aged 8-18 years. Patients completed the Children's Depression Inventory (CDI), Screening for Child Anxiety Related Disorders (SCARED), Pediatric Quality of Life Inventory Generic Core Scale (PedsQL-GC), and Visual Analog Scale of pain intensity. Their parents completed the Pediatric Quality of Life Family Impact module (PedsQL family impact). Results Of 91 patients, the median disease duration was 3.4 years (IQR 3.5), and the median SLE disease activity index 2000 score was 2 (IQR 6). The prevalence of clinically significant depression (CDI > 15) and clinically significant anxiety (SCARED >= 25) were 31.9% and 49.5%, respectively. Coexisting clinically significant depression and anxiety were found in 26 patients (28.6%). In multivariable analyses, older age at diagnosis was associated with clinically significant depression (OR 1.56, 95% CI 1.12-2.16, p = 0.008), while organ damage (OR 4.27, 95% CI: 1.19-15.31, p = 0.026) and pain score (OR 1.61, 95% CI: 1.11-2.32, p = 0.012) were associated with clinically significant anxiety. Patients with clinically significant depression or anxiety had significantly lower PedsQL-GC and PedsQL family impact scores compared to those without these symptoms. Conclusions These results suggest that depression and anxiety are prevalent in cSLE and have negative impacts on HRQOL and family. Physicians should be aware of the presence of these psychological symptoms, particularly in patients with risk factors. Providing psychological counseling and prompt referral to psychiatrists could enhance HRQOL and family functioning.