Dr Emer Holohan, the wife of Chief Medical Officer Dr Tony Holohan, passed away at Our Lady's Hospice in Harold's Cross in Dublin.
Dr Holohan, who died after a long illness, is also survived by her two children.
In a statement, Taoiseach Micheál Martin said: "Our thoughts and prayers are with Chief Medical Officer Dr Tony Holohan, and his children, Clodagh and Ronan, today following the sad passing of his wife Emer.
"Dr Emer Holohan made a significant contribution to the health service, including her work on the Health Strategy when I was Minister for Health.
"Tony and his entire family have given so much to this country since the start of the pandemic.
"At this time, I would ask for as much space and privacy to be given to them as possible," added Mr Martin.