This study investigates the causal relationships between sedentary behavior (SB), physical activity (PA), sleep duration (SD), and obesity using Mendelian randomization (MR). The authors used genetic variants associated with SB, PA, and SD from Genome-Wide Association Studies (GWAS) and obesity data from FinnGen. The primary MR analysis employed the Instrumental Variable Weighted (IVW) method, with sensitivity tests including Cochran Q, MR-Egger intercepts, and MR-Radial. The eQTL analysis was conducted to identify significant genetic associations and biological pathways in obesity-related tissues. The results revealed a causal relationship between four specific SBs—television watching, computer use, leisure screen time (LST), and driving—and obesity. Specifically, increased genetic liability to these SBs was associated with an increased risk of obesity. However, no causal relationships were observed between SB at work, sedentary commuting, PA, SD, and obesity. The eQTL analysis identified strong associations between specific genes (RPS26, TTC12, CCDC92, NICN1) and SNPs in subcutaneous and visceral adipose tissues, which are associated with these SBs. The study concludes that reducing specific SBs (especially LST, television watching, computer use, and driving) could be a more targeted approach to combat obesity compared to encouraging regular PA and SD. The findings provide valuable insights into potential interventions and highlight the importance of addressing SB in public health strategies.This study investigates the causal relationships between sedentary behavior (SB), physical activity (PA), sleep duration (SD), and obesity using Mendelian randomization (MR). The authors used genetic variants associated with SB, PA, and SD from Genome-Wide Association Studies (GWAS) and obesity data from FinnGen. The primary MR analysis employed the Instrumental Variable Weighted (IVW) method, with sensitivity tests including Cochran Q, MR-Egger intercepts, and MR-Radial. The eQTL analysis was conducted to identify significant genetic associations and biological pathways in obesity-related tissues. The results revealed a causal relationship between four specific SBs—television watching, computer use, leisure screen time (LST), and driving—and obesity. Specifically, increased genetic liability to these SBs was associated with an increased risk of obesity. However, no causal relationships were observed between SB at work, sedentary commuting, PA, SD, and obesity. The eQTL analysis identified strong associations between specific genes (RPS26, TTC12, CCDC92, NICN1) and SNPs in subcutaneous and visceral adipose tissues, which are associated with these SBs. The study concludes that reducing specific SBs (especially LST, television watching, computer use, and driving) could be a more targeted approach to combat obesity compared to encouraging regular PA and SD. The findings provide valuable insights into potential interventions and highlight the importance of addressing SB in public health strategies.