The government has announced the development through social media, adding that the appointment is with immediate effect.
It follows the dismissal of George Chaponda as minister, after his implication in the ADMARC maize scandal.
After Firing Chaponda, Mutharika had directed that all issues involving the ministry be addressed to his office.
Critics have since been urging the president to find a replacement for Chaponda, arguing that the ministry is crucial, and needs undivided attention.
Masi is a member of the ruling Democratic Progressive Party (DPP) and Member of Parliament for Lilongwe City West.
He was appointed Deputy Minister of Home Affairs and Internal Security in April last year.
It remains to be seen whether Mutharika will also appoint someone to head the ministry as the position is still vacant.