BACKGROUND: A second wave of COVID-19 cases in autumn, 2020, in England led to localised, tiered restrictions (so-called alert levels) and, subsequently, a second national lockdown. We examined the impact of these tiered restrictions, and alternatives for lockdown stringency, timing, and duration, on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and hospital admissions and deaths from COVID-19. METHODS: We fit an age-structured mathematical model of SARS-CoV-2 transmission to data on hospital admissions and hospital bed occupancy (ISARIC4C/COVID-19 Clinical Information Network, National Health Service [NHS] England), seroprevalence (Office for National Statistics, UK Biobank, REACT-2 study), virology (REACT-1 study), and deaths (Public Health England) across the seven NHS England regions from March 1, to Oct 13, 2020. We analysed mobility (Google Community Mobility) and social contact (CoMix study) data to estimate the effect of tiered restrictions implemented in England, and of lockdowns implemented in Northern Ireland and Wales, in October, 2020, and projected epidemiological scenarios for England up to March 31, 2021. FINDINGS: We estimated a reduction in the effective reproduction number (Rt) of 2% (95% credible interval [CrI] 0-4) for tier 2, 10% (6-14) for tier 3, 35% (30-41) for a Northern Ireland-stringency lockdown with schools closed, and 44% (37-49) for a Wales-stringency lockdown with schools closed. From Oct 1, 2020, to March 31, 2021, a projected COVID-19 epidemic without tiered restrictions or lockdown results in 280 000 (95% projection interval 274 000-287 000) hospital admissions and 58 500 (55 800-61 100) deaths. Tiered restrictions would reduce hospital admissions to 238 000 (231 000-245 000) and deaths to 48 600 (46 400-50 700). From Nov 5, 2020, a 4-week Wales-type lockdown with schools remaining open-similar to the lockdown measures announced in England in November, 2020-was projected to further reduce hospital admissions to 186 000 (179 000-193 000) and deaths to 36 800 (34 900-38 800). Closing schools was projected to further reduce hospital admissions to 157 000 (152 000-163 000) and deaths to 30 300 (29 000-31 900). A projected lockdown of greater than 4 weeks would reduce deaths but would bring diminishing returns in reducing peak pressure on hospital services. An earlier lockdown would have reduced deaths and hospitalisations in the short term, but would lead to a faster resurgence in cases after January, 2021. In a post-hoc analysis, we estimated that the second lockdown in England (Nov 5-Dec 2) reduced Rt by 22% (95% CrI 15-29), rather than the 32% (25-39) reduction estimated for a Wales-stringency lockdown with schools open. INTERPRETATION: Lockdown measures outperform less stringent restrictions in reducing cumulative deaths. We projected that the lockdown policy announced to commence in England on Nov 5, with a similar stringency to the lockdown adopted in Wales, would reduce pressure on the health service and would be well timed to suppress deaths over the winter period, while allowing schools to remain open. Following completion of the analysis, we analysed new data from November, 2020, and found that despite similarities in policy, the second lockdown in England had a smaller impact on behaviour than did the second lockdown in Wales, resulting in more deaths and hospitalisations than we originally projected when focusing on a Wales-stringency scenario for the lockdown. FUNDING: Horizon 2020, UK Medical Research Council, and the National Institute for Health Research.