The Heat eliminated the Knicks in five games and will now meet Indiana in the Eastern Conference semifinals. Miami won three of its four regular-season meetings with the Pacers this year.
Miami owned a 14-point lead heading into the fourth period, having methodically built its advantage thanks to a dominance at the foul line and quality outside shooting.
The Heat made 9-of-19 from 3-point range and converted 29-of-34 free throws. James was 13-of-15 from the line.
Chris Bosh and Dwyane Wade both had 19 points for the Heat.
New York's second post-season appearance in as many years was a short one, ending a season highlighted by the mid-season emergence of point guard Jeremy Lin.
Lin, however, has not played since March following surgery to repair torn knee cartilage. The Knicks' two straight trips to the playoffs have come after they missed the post-season for six consecutive seasons.
New York at least ended its NBA-record streak of 13 consecutive playoff in this series with a victory in Game 4.
The 106 points produced by the Heat Wednesday were the most Miami scored in the series.