BackgroundPrevious studies have shown that lifestyle was associated with depression. Thus, the aim of this study was to examine the causality between multiple lifestyles and depression by Mendelian randomization (MR) analysis.MethodsThe single-nucleotide polymorphisms (SNPs) of depression, alcoholic drinks per week, sleeplessness or insomnia, body mass index (BMI), mood swings, weekly usage of mobile phone in the last 3 months, beef intake, cooked vegetable intake, and “smoking status: never” were acquired from the Integrative Epidemiology Unit Open genome-wide association study database. Causal effects of eight exposure factors and depression were investigated using MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode, and results were primarily referred to IVW. Subsequently, univariable MR (UVMR) analysis was performed on eight exposure factors and depression, separately. In addition, sensitivity analysis, including heterogeneity test, horizontal pleiotropy, and leave-one-out (LOO) methods, was conducted to evaluate the stability of MR results. Furthermore, multivariable MR (MVMR) analysis was carried out.ResultsUVMR analysis revealed that all eight exposure factors were causally associated with depression; alcoholic drinks per week, sleeplessness or insomnia, BMI, mood swings, weekly usage of mobile phone in the last 3 months, and cooked vegetable intake were risk factors, and beef intake and “smoking status: never” were protection factors. Heterogeneity tests revealed no heterogeneity for alcoholic drinks per week, sleeplessness or insomnia, mood swings, weekly usage of mobile phone in the last 3 months, and cooked vegetable intake. Meanwhile, there was no horizontal pleiotropy in UVMR, and LOO analysis verified that univariable analysis results were reliable. Moreover, MVMR analysis indicated that mood swings and weekly usage of mobile phone in the last 3 months were risk factors, and beef intake was a protection factor for depression when multiple factors occurred at the same time.ConclusionAlcoholic drinks per week, sleeplessness or insomnia, BMI, mood swings, weekly usage of mobile phone in the last 3 months, and cooked vegetable intake were risk factors, and beef intake and “smoking status: never” were protection factors. In addition, mood swings, weekly usage of mobile phone in the last 3 months, and beef intake had a direct effect on depression when multiple factors occurred simultaneously.