"aftermost fore-and-aft sail of a three-masted ship," early 15c., mesan, via French misaine "foresail, foremast," altered (by influence of Italian mezzana "mizzen") from Old French migenne, from Catalan mitjana, from Latin medianus "of the middle" (from PIE root *medhyo- "middle").
The sense of the English and Italian words agree, but the etymology is off because the "middle" mast on a ship is the mainmast. Perhaps it refers to a sail of "middle" size, or the thing described changed. Klein suggests an alternate etymology of the French word, from Arabic via Italian. The mizzen-mast (late 15c.) supports the mizzen-sail.