BACKGROUND: Preoperative mental health and depression have been shown to negatively impact patient-reported outcome measures after a broad array of orthopaedic procedures including total ankle arthroplasty. The hypothesis for this study was that decreased Short Form (SF)-36 Mental Component Summary (MCS) scores will modulate the impact of depression on patient-reported outcome measures after total ankle arthroplasty. METHODS: All patients undergoing primary total ankle arthroplasty between January 2007 and December 2016 who were enrolled into a prospective outcomes study and who had at least 1-year minimum study follow-up were retrospectively reviewed. Patients were separated into 4 groups based on the presence or absence of an SF-36 MCS score of <35 points and diagnosis of depression. SF-36 Physical Component Summary (PCS) and MCS scores, Short Musculoskeletal Function Assessment (SMFA) function and bother components, and visual analog scale (VAS) pain were collected preoperatively and in the 1 to 2-year follow-up. The Wilcoxon rank sum was used to assess differences in outcomes by depression and low preoperative MCS scores. Multivariable models were then constructed to evaluate between-group differences in change scores according to preoperative SF-36 MCS scores and a diagnosis of depression, with adjustment for baseline patient and treatment characteristics. RESULTS: Patients with depression and those with low preoperative MCS scores had significantly worse final outcome scores along with reduced improvement in SF-36 PCS and VAS pain scores compared with patients without these risk factors. Among patients with depression, low preoperative MCS scores helped to differentiate patients with poor final outcome scores. Similarly, in patients with low preoperative MCS scores, depression helped to differentiate patients with poor final outcome scores. CONCLUSIONS: Although patients achieved significant improvements in functional outcomes regardless of cohort, decreased preoperative mental health modulated the impact of depression on outcomes. Patients with diminished preoperative mental health and depression are at an increased risk for sustaining smaller improvements in outcomes. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.