The announcement means Manx patients will be able to continue to use the lifeline service when requiring treatment in the UK.
The Exeter-based airline currently operates the patient transfer service to Liverpool, carrying about 13,000 people a year.
Three services to Liverpool at weekends are also scheduled from March.
In total, the airline will operate 57 flights a week from the Isle of Man, with routes to Manchester and Birmingham also confirmed.
Five weekday flights to and from Manchester have been announced alongside daily flights to and from Birmingham.
Flybe's Paul Simmons said:
"Flybe remains fully committed in continuing to serve its Isle of Man customers and we hope that today's confirmation will serve to reinforce this."
Infrastructure Minister David Cretney said:
"I am pleased that they are continuing to serve both North West destinations.
"The one disappointed aspect is that Birmingham will be less well served than it is presently."
In November, Flybe announced its Isle of Man base would close this year with the loss of 50 jobs bringing about urgent talks with the island's Chief Minister.
The firm is looking to close six bases, including the Isle of Man, to save £85m over the next few years.