President Saied issued two decrees, the first terminating Charfeddine's duties and a second appointing Kamel Feki as Interior Minister, the presidency said in a statement on Friday night.
Mr. Feki is a law graduate and a former executive of the Ministry of Finance. He has held the post of prefect of Tunis since late 2021.
His nomination comes few hours after Taoufik Charfeddine, a close aide of President Kais Saied, announced he had resigned to spend more time with his children following the death of his wife last year.
Charfeddine, 54, who had held his post since October 2021, told reporters he wished to thank the president for "his understanding and for allowing me to be relieved of my duties".
The minister's wife died in a fire caused by a gas leak in their home in June last year.
A former lawyer, Charfeddine was a key figure in the election campaign that propelled the previously little known Saied to the presidency in 2019.
After Saied froze parliament and sacked the then government in a dramatic July 2021 move against the sole democracy to emerge from the Arab Spring uprisings, Charfeddine became a close adviser.
As the president pushed through sweeping changes to the country's political system, concentrating near-total power in his office, Charfeddine was one of the most outspoken defenders of his power grab.
Saied's office regularly released video footage of the two men's frequent meetings in the presidential palace.
On March 8, more than 30 Tunisian non-governmental organisations demanded an apology from the minister after he branded as "traitors" the president's many critics in the private sector, the media and trade unions.
They accused him of using the "language of threat and intimidation" to "sow division" among Tunisians as part of a "dangerous populist discourse that foreshadows a police state" like the one overthrown in the country's 2011 uprising.