Two nights after the Knicks surrendered a Madison Square Garden-record 61 points to Kobe Bryant of the Los Angeles Lakers, James produced his season-high total.
He also had 11 assists and 10 rebounds, becoming the first player since Kareem Abdul-Jabbar in 1975 to put together a triple-double while scoring 50 points.
New York also became the first NBA team in 47 years to give up back-to-back 50-point games.
Cleveland, which won for the eighth time in nine games, got 15 points from Zydrunas Ilgauskas and 12 from Wally Szczerbiak.
Al Harrington had a season-high 39 for New York, which has lost two straight after winning six of seven.
James wrapped up the victory by hitting two free throws with 22 seconds to play that gave Cleveland a six-point advantage.