Background: The Lancet Commission on global access to palliative care and pain relief introduced the concept of serious health-related suffering (SHS) to measure the worldwide dearth of palliative care. This Article provides an extended analysis of SHS from 1990 to 2021 and the corresponding global palliative care need. Methods: This Article is the first to apply the SHS 2·0 method published in 2024, incorporating prevalence data from the Global Burden of Diseases, Injuries, and Risk Factors Study to improve non-decedent estimates that account for country-level epidemiological variation; adjusting for non-decedent double counting of HIV/AIDS, cancer, cerebrovascular disease, and dementia; improving the non-decedent estimates for cancer using survivorship data from the Global Cancer Observatory and for HIV/AIDS incorporating access to antiretroviral therapy; differentiating by sex; considering more specific age groups allowing for better estimates, especially in children; and adding endocrine, metabolic, blood, and immune disorders to the health conditions causing SHS. We describe SHS trends globally and within country income groups, differentiating among decedents and non-decedents, by health conditions, sex, and across child and adult age groups. Findings: The SHS global burden increased by 74% between 1990 and 2021 to almost 73·5 million individuals, with population growth accounting for only half of that increase. Low-income and middle-income countries (LMICs) accounted for 80% of SHS, with an increase of 83% from 1990 to 2021 compared with a 46% increase in high-income countries (HICs). Between 1990 and 2021, the decedent burden increased by 35%, whereas SHS in non-decedents more than doubled, accounting for 63% of SHS by 2021. The proportion of SHS from communicable diseases declined, especially in LMICs; however, the absolute number stayed relatively stable and even increased from 2019 to 2021 with the start of the COVID-19 pandemic. SHS from non-communicable diseases drastically increased, led by cancer (excluding leukaemia), cardiovascular diseases, and dementia in HICs. HIV/AIDS continued to be a major contributor, accounting for a substantial share of SHS in sub-Saharan Africa. The share of SHS in children decreased from 25% of SHS in 1990 to 14% in 2021 and accounted for 33% of SHS in low-income countries, compared with 2% in HICs. In 2021, SHS in low-income countries was concentrated in female individuals aged 20–49 years (affecting 59% of this population); in HICs, SHS was concentrated in female individuals aged 70 years and older (affecting 54% of this population and probably related to dementia). Interpretation: SHS and the associated need for palliative care is a major and persistent but not insurmountable challenge for health systems worldwide. Our findings highlight the urgency to both reduce the avoidable SHS burden through prevention and treatment, and guarantee comprehensive, universal access to palliative care as an equity and health system imperative, especially in LMICs. Funding: University of Miami, USA; Cancer Pain Relief Committee; Medical Research Council; GDS.