<b><i>Introduction:</i></b> Psychological adjustment to chronic health conditions is important, as poor adjustment predicts a range of adverse medical and psychosocial outcomes. Psychological treatments demonstrate efficacy for people with chronic health conditions, but existing research takes a disorder-specific approach and they are predominately delivered in face-to-face contexts. The internet and remotely delivered treatments have the potential to overcome barriers to accessing traditional face-to-face treatment. <b><i>Objective:</i></b> The current study examined the efficacy and acceptability of an internet-delivered transdiagnostic psychological intervention to promote adjustment to illness, based on cognitive behaviour therapy principles. <b><i>Methods:</i></b> In a two-arm randomised controlled trial, participants (<i>n</i> = 676) were randomly allocated to the 8-week intervention or a waitlist control. Treatment included five core lessons, homework tasks, additional resources, and weekly contact with a psychologist. Primary outcomes included depression, anxiety, and disability, assessed at pre-treatment, post-treatment, 3-month follow-up, and 12-month follow-up. <b><i>Results:</i></b> The treatment group reported significantly greater improvements in depression (between-groups <i>d =</i> 0.47), anxiety (<i>d</i> = 0.32), and disability (<i>d</i> = 0.17) at post-treatment (all <i>ps</i> &#x3c;0.001). Improvements were sustained over the 3-month and 12-month follow-ups. High treatment completion rates (69%) and levels of satisfaction (86%) were reported by participants in treatment. The intervention required a mean clinician time of 56.70 min per participant. <b><i>Conclusions:</i></b> The findings provide preliminary and tentative support for the potential of internet-delivered transdiagnostic interventions to promote adjustment to chronic health conditions. Further research using robust control groups, and exploring the generalisability of findings, is needed before firm conclusions can be drawn.