Azerbaijan's Kamran Shakhsuvarly and Mexico's Misael Rodriguez, his country's first medallist in the division since 1968, took the bronze medals as losing semi-finalists.
Fighting half an hour after compatriot Robeisy Ramirez had won bantamweight gold, Lopez ensured Cuba won two of the day's three finals by taking the opening rounds before easing off slightly in the third.
The top seed coming into the tournament, Lopez always looked the more polished fighter in what was a repeat of the 2015 world championship final and he closed out the draw with a 3-0 win.
The 23-year-old caught Melikuziev with his arm in the third round, leading to a brief pause while the Uzbek had medical attention for a gash above his eye.
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Cuba have now won middleweight gold five times, equalling the United States and Britain.
"There was some information from people in the stands through signals that I was ahead and that encouraged me and I knew the victory was in my hands," said Lopez, who celebrated with a forward roll on the canvas.
Japan's Ryoto Murata won the title in 2012 and then turned professional.
(Editing by Nina Chestney and Clare Fallon)
