Mzuzu sits on the M1, the main road that runs the length of Malawi from Karonga in the north to Blantyre in the south. The road is tarred and in reasonable condition; allow about six hours from Lilongwe by car or AXA executive coach (the coaches run twice daily and are by far the most comfortable bus option). From Nkhata Bay on the lake, it is a slow, scenic two hours up the escarpment.
Mzuzu Airport is 4 km west of town and has flights several times a week to Lilongwe with Malawian Airlines, plus a twice-weekly service to Nyika that lets you skip the long drive in. Internal flights are not cheap by African standards but save a full day each way over road travel.