Francisco Javier Terrientes "today presented his resignation from his post for professional reasons," the government said in a statement.
It added that President Juan Carlos Varela had appointed the deputy health minister, Miguel Mayo, to take Terrientes' place.
Panama's hospitals and clinics are overrun by people wanting vaccinations against the A(H1N1) flu virus which has proved particularly dangerous this year in Panama.
Since early May, 22 people have died of the virus and 671 were hospitalized, of whom nearly half remain admitted and 38 are in intensive care.
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A(H1N1), or swine flu, was first detected in 2009, spreading from the United States to Mexico and prompting the World Health Organization to declare a pandemic that year.
This subtype of the flu virus causes a respiratory infection whose symptoms can be mild or fatal.
In tropical zones such as Panama, it can occur year round, especially during the rainy season, which has now begun in the Central American country.