PURPOSE Many hospitals have established goals-of-care programs in response to the coronavirus disease 2019 pandemic; however, few have reported their outcomes. We examined the impact of a multicomponent interdisciplinary goals-of-care program on intensive care unit (ICU) mortality and hospital outcomes for medical inpatients with cancer. METHODS This single-center study with a quasi-experimental design included consecutive adult patients with cancer admitted to medical units at the MD Anderson Cancer Center, TX, during the 8-month preimplementation (May 1, 2019-December 31, 2019) and postimplementation period (May 1, 2020-December 31, 2020). The primary outcome was ICU mortality. Secondary outcomes included ICU length of stay, hospital mortality, and proportion/timing of care plan documentation. Propensity score weighting was used to adjust for differences in potential covariates, including age, sex, cancer diagnosis, race/ethnicity, and Sequential Organ Failure Assessment score. RESULTS This study involved 12,941 hospitalized patients with cancer (pre n = 6,977; post n = 5,964) including 1,365 ICU admissions (pre n = 727; post n = 638). After multicomponent goals-of-care program initiation, we observed a significant reduction in ICU mortality (28.2% v 21.9%; change −6.3%, 95% CI, −9.6 to −3.1; P = .0001). We also observed significant decreases in length of ICU stay (mean change −1.4 days, 95% CI, −2.0 to −0.7; P < .0001) and in-hospital mortality (7% v 6.1%, mean change −0.9%, 95% CI, −1.5 to −0.3; P = .004). The proportion of hospitalized patients with an in-hospital do-not-resuscitate order increased significantly from 14.7% to 19.6% after implementation (odds ratio, 1.4; 95% CI, 1.3 to 1.5; P < .0001), and do-not-resuscitate order was established earlier (mean difference −3.0 days, 95% CI, −3.9 to −2.1; P < .0001). CONCLUSION This study showed improvement in hospital outcomes and care plan documentation after implementation of a system-wide, multicomponent goals-of-care intervention.