Manzano entered politics in 1998 when he ran for Vice Mayor of Makati City. He garnered a majority of votes in the election, but his proclamation was suspended due to a case filed which alleged that he was not a citizen of the Philippines. The Comelec eventually ruled that he was indeed a Filipino citizen, clearing the way for his proclamation as Vice Mayor. Following a three-year term, he ran an unsuccessful campaign for Mayor of Makati City in 2001, losing to Jejomar Binay.

In 2004, Manzano became the first chairman of the Optical Media Board, a government agency tasked with combating optical media piracy. He resigned the position in August 2009.

On November 13, 2009, it was announced that Manzano will be Lakas-Kampi-CMD�s candidate for Vice President in the May 2010 election, and the running mate of presidential candidate Gilbert Teodoro.