Background The ability to understand factors associated with an increased duration of missed work postoperatively could be used to more effectively select patients with the greatest opportunity for a successful outcome. We set out to determine the effect of preoperative depression on postoperative return to work in patients undergoing transforaminal lumbar interbody fusion (TLIF) for degenerative spondylolisthesis. Methods Fifty-eight patients undergoing TLIF for symptomatic grade I degenerative lumbar spondylolisthesis were included in this analysis. Patient demographics, clinical presentation, indications for surgery, radiologic studies, and operative variables were assessed for each case. Patient-assessed outcome measures were obtained prospectively at baseline and 2 years postoperatively. To understand the factors associated with prolonged return to work, univariate linear regression analysis and stepwise multivariate Cox proportional hazards model was used. Results All patient-reported outcomes assessed were significantly improved 2 years after TLIF ( P < 0.001). Of the 32 patients working preoperatively, 26 (81%) returned to work postoperatively. Median time to return to work was 56 days (range, 10–150 days). Independent of patient age; preoperative pain, disability, and quality of life; and extent of postoperative improvement, increased preoperative Zung depression score remained associated with prolonged return to work ( P  = 0.02). Conclusions Independent of postoperative improvement in pain, disability, and quality of life, the extent of preoperative depression was an independent predictor of time to return to work in patients undergoing TLIF for spondylolisthesis, suggesting that regardless of how successful TLIF surgery may be at improving a patient's pain, disability, or quality of life, greater depression will delay or prohibit their ability to return to work postoperatively.