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ObjectiveLow back pain is a prevalent and debilitating condition worldwide, with significant implications for individuals’ quality of life and productivity. The aim of this study was to assess the relationship between mood instability and the risk of developing chronic low back pain, using a rigorously designed mendelian randomization methodology.MethodThe study incorporated both univariate and multivariate mendelian randomization to analysis the causal relationship between mood instability and the risk of developing chronic low back pain. The data on mood instability from the Integrative Epidemiology Unit (IEU) opened Genome-Wide Association Studies (GWAS) project (IEU-opened GWAS project). Data on low back pain were collected from two sources: One source is the IEU open GWAS project (discovery data). Another source is a GWAS meta-analysis (replication data). Inverse variance weighted method, weighted median method, MR-Egger regression, and mendelian randomization pleiotropy residual sum and outlier method were used for mendelian randomization analysis.ResultThe univariable mendelian randomization analysis shows a statistically significant correlation between mood instability and the risk of low back pain. Several methods were performed, including inverse variance weighting (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785–7.039, p = 0.000; replication data: odds ratio = 3.167, 95% confidence interval = 2.476–4.052, p = 0.000), MR-Egger (discovery data: odds ratio = 7.178, 95% confidence interval = 0.057–909.525, p = 0.429; replication data: odds ratio = 2.262, 95% confidence interval = 0.580–8.825, p = 0.246), weighted median (discovery data: odds ratio = 2.730, 95% confidence interval = 1.112–6.702, p = 0.028; replication data: odds ratio = 3.243, 95% confidence interval = 2.378–4.422, p = 0.000), MR-PRESSO (discovery data: odds ratio = 3.544, 95% confidence interval = 1.785–7.039, p = 0.001; replication data: odds ratio = 3.167, 95% confidence interval = 2.476–4.052, p = 0.000) methods. The results were consistent across these methods. The results obtained from discovery data are consistent with those obtained from discovery data. In the multivariable mendelian randomization, after adjusting for various covariates such as body mass index, current tobacco smoking, alcohol intake frequency, Total body bone mineral density, and vigorous physical activity, there is a consistent correlation between mood instability and chronic low back pain.ConclusionThis study provides robust evidence supporting a causal relationship between mood instability and the development of low back pain. Our findings suggest that addressing mood instability may play a crucial role in prevention and management strategies for individuals experiencing low back pain.