Background: Patients with and without cancer are frequently hospitalized, and have specialist palliative care needs. In-hospital mortality can serve as a quality indicator of acute care. Trends in acute care outcomes have not previously been evaluated in patients with confirmed specialist palliative care needs or between diagnostic groups. Aim: To compare trends in discharge location between hospitalized patients with and without cancer who received specialist palliative care. Design: Retrospective cohort study. Association between diagnosis (cancer, non-cancer) and in-hospital mortality was assessed using multivariable logistic regression, controlling for demographic, clinical, and admission-specific information. Setting/participants: Patients who received specialist palliative care at an academic tertiary hospital in Toronto, Canada from 2013 to 2019. Results: The cohort comprised 6846 patients, 5024 with and 1822 without cancer. A higher proportion of patients without cancer had a Palliative Performance Scale score <30%, anticipated prognosis of <1 month, and were referred for end-of-life care (all p < 0.001). The adjusted odds of dying in hospital was 1.24-times higher among patients without cancer (95% CI: 1.05–1.46; p = 0.011). Though the proportion of patients without cancer who died in hospital decreased by 8.4% from 2013 to 2019, this proportion (41.2%) remained substantially higher compared to patients with cancer (14.0%) in 2019. Conclusions: Hospitalized patients without cancer were referred to specialist palliative care at a lower functional status, a poorer anticipated prognosis, and more likely for end-of-life care; and were more likely to die in hospital. Future studies are required to determine whether a proportion of hospital deaths in patients without cancer represent goal-discordant end-of-life care.