Totterdell is currently the group chief executive at St George's, Epsom and St Helier University Hospitals and Health Group.
She will succeed Judith Paget, who is taking up a new role as director general for strategy within Welsh Government to strengthen strategic planning and delivery as the organisation enters a period of significant change.
Health secretary, Jeremy Miles, said: ‘I look forward to working with Jacqueline as we focus on delivery and improvement and help the NHS adapt for the future. This includes building on the progress we're making in Wales on waiting times, and to go further, to deliver the faster access to treatment that people in Wales want.'
Totterdell said: ‘Being able to improve services on a whole-country level is what attracted me to this role and I'm really looking forward to working with everyone to make a real difference for people in Wales.'