Abstract Background Little is known about the dose and pattern of moderate-to-vigorous physical activity (MVPA) to prevent depression. We aimed to assess the prospective association of dose and pattern of accelerometer-derived MVPA with the risk of diagnosed depression. Methods We included 74,715 adults aged 40–69 years from the UK Biobank cohort who were free of severe disease at baseline and participated in accelerometer measurements (mean age 55.2 years [SD 7.8]; 58% women). MVPA at baseline was derived through 1-week wrist-worn accelerometry. Diagnosed depression was defined by hospitalization with ICD-10 codes F32.0-F32.A. Restricted cubic splines and Cox regression determined the prospective association of dose and pattern of MVPA with the risk of incident depression. Results Over a median 7.9-year follow-up, there were 3,089 (4.1%) incident cases of depression. Higher doses of MVPA were curvilinearly associated with lower depression risk, with the largest minute-per-minute added benefits occurring between 5 (HR 0.99 [95% CI 0.96–0.99]) and 280 (HR 0.67 [95% CI 0.60–0.74]) minutes per week (reference: 0 MVPA minutes). Conclusion Regardless of pattern, higher doses of MVPA were associated with lower depression risk in a curvilinear manner, with the greatest incremental benefit per minute occurring during the first 4–5 h per week. Optimal benefits occurred around 15 h/week.