The plane picked up the signal in the same area where an Australian vessel detected audio pings earlier this week, officials said.
The signal would require further analysis, but could have been from a “man-made source”, officials said.
Flight MH370 vanished on March 8, with 239 people on board.
The search zone was tightened on Thursday after a US navy “towed pinger locator” picked up audio signals in the area, sparking hopes that the plane’s black box was in the area.
Australian vessel Ocean Shield picked up four acoustic signals in the area, twice over the weekend and twice on Tuesday.
Speaking after the latest possible signal was detected, retired Air Chief Marshal Angus Houston, who is leading search efforts, said: “The acoustic data will require further analysis overnight but shows potential of being from a man-made source.”
Up to 14 planes and 13 ships are involved in Thursday’s search, scouring an area of 22 300 sq miles, around 1,400 miles north-west of Perth. It is the smallest designated area in the hunt to date.
Planes have dropped buoys equipped with hydrophone listening devices into the water to help pick up signals.
The batteries on the black box only last about a month, so teams need to work quickly to track the audio signals before they stop broadcasting.
Malaysia has come under criticism for its handling of the search, with families of the passengers on the plane accusing the authorities of a lack of transparency.
The investigation came under further scrutiny after it emerged that the final words from the plane were “good night Malaysian three seven zero”, and not “all right, good night”, as previously reported by the government.
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