Adherence to government COVID-19-related instructions is reported to be high, but the psychosocial impacts of measures such as self-isolation and physical distancing could undermine long-term adherence to containment measures. The first step in designing interventions to mitigate the impacts of adhering to COVID-19-related instructions is to identify what are the most prevalent challenges and what characterises the people facing them. A cross-sectional survey was administered to a representative sample of the UK population (N = 2252), of whom n = 2139 (94.9%) reported adhering to the UK government's COVID-19-related instructions, and were included in the final analysis. Data were analysed using descriptive statistics and binary logistic regression. Of the people who reported adhering to UK government's COVID-19-related instructions, 80.3% reported experiencing challenges. Adults aged 55 years or over (OR = 1.939, 95%CI 1.331–2.825) and men (OR = 0.489, 95%CI 0.393–0.608) were least likely to report challenges. Adjusting to changes in daily routine (reported by 48.7% of the sample), mental health (reported by 41.4% of the sample) and physical health (reported by 31.5% of the sample) were the most prevalent challenges. For the first time, the present study quantifies the extent to which people experienced challenges when adhering to government COVID-19-related instructions. Few people reported experiencing no challenges when adhering to COVID-19-related instructions. Interventions to address the effects of changes in daily routine, mental health challenges, and physical health challenges should be prioritised, with a focus on key subgroups including women, younger adults, and people without care commitments.