Background Public health restrictions due to the COVID‐19 (SARS CoV‐2) pandemic have disproportionately affected informal caregivers of people living with long term health conditions. We aimed to explore levels of care burden, loneliness, and social isolation among caregivers of people with enduring physical and brain health conditions in English‐speaking regions worldwide, by investigating outcomes before and during the COVID‐19 pandemic. Methods A cross‐sectional anonymous online survey data from 2287 English‐speaking caregivers of people with long term health conditions from four English‐speaking regions (UK, Ireland, USA, New Zealand) included measures of care burden, loneliness, and social isolation, reported before and during the COVID‐19 pandemic. Analyses were descriptive, followed by an ordinal regression model for predictors of burden. Results Compared to pre‐pandemic levels, all caregivers experienced a significant increase in burden, loneliness, and isolation. Caregivers of people with both brain health and physical conditions were the most burdened and had the highest levels of loneliness and isolation compared to caregivers of people with either a brain health or physical condition only. The increase in care burden among caregivers of people with brain health challenges was associated with caregiver's gender, moderate and severe emotional loneliness, magnitude and frequency of isolation during the pandemic, and care circumstances (cohabitation with the care recipient, restrictions on the ability to provide care). Conclusions Health and social care interventions should target caregivers' care circumstances and psychological outcomes, particularly in women, accounting for the significant additional burden of care, loneliness, and isolation resulting from pandemic‐related restrictions. Key points This study highlights the significant negative impact that COVID‐19‐related restrictions have had on informal caregivers of people with enduring health conditions in four English speaking regions, globally. Heightened levels of burden, loneliness, and social isolation occurred during the pandemic compared to pre‐pandemic in caregivers of people with enduring physical and brain health or physical health conditions. The increase in burden in caregivers of people with brain health conditions was associated with caregiver factors (including gender, emotional loneliness, and increase in social isolation) and pandemic‐related external factors, such as cohabitation with the care recipient and the impact of COVID‐19‐related restrictions on the ability to provide care. These findings have implications for policy development and healthcare interventions to target care circumstances and psychosocial outcomes of informal caregivers and ensure their equitable access to social support, taking into consideration pandemic‐related changes.