Hosszu powered through in the freestyle leg to clock four minutes 33.90 seconds on Sunday morning. The 28-year-old finished 1.39 seconds ahead of her nearest challenger, Mireia Belmonte of Spain.
Hosszu is aiming to add the 400 medley title to the 200m individual gold she won earlier in the week, alongside silver in the 200m backstroke and bronze in the 200m butterfly.
Victory in the final later on Sunday would see her become the first woman to claim four medals in the event.
Chase Kalisz of the United States will also aim to secure a clean sweep of individual medley titles in the men's 400m.
Kalisz, who also won the 200m medley gold, coasted through to the final with a time of four minutes 09.79 seconds.
Max Litchfield of Britain will race alongside Kalisz in the final after qualifying second, with Hungary's local hope David Verraszto third.
The women's medley 4x100m saw the United States head qualifying into the final thanks to a swift time of three minutes 55.95 seconds.
A double medley gold for the medal table leaders looks in the offing after the U.S. men's quartet recorded the leading time in their 4x100m heat.
The U.S. recorded three minutes 29.66 seconds, with Japan, Russia and Britain set to challenge for medals.
America's title defence will be aided further in the final when 20-year-old Calaeb Dressel will line up in the medley team as he attempts to match Michael Phelps's record of seven golds at one edition of world championships.
Dressel currently holds six golds after a record-breaking week in the Hungarian capital while Phelps, the most decorated Olympian of all time, claimed a seven-gold haul in Melbourne 10 years ago.
However, men's medley team changes will occur elsewhere too.
Britain, the Olympic silver medallists, could scupper Dressel's hopes, with Adam Peaty also expected to be included in their final quartet. The Briton won individual 50m and 100m breaststroke gold earlier in the week.
(Editing by Sudipto Ganguly)
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