Around 3,000 patients died needlessly last year as a result of poor care, Jeremy Hunt said as he called on the health service to tackle the "silent scandal of errors".
The Health Secretary confirmed that nearly 500,000 people were also harmed unnecessarily while the NHS also recorded 326 "never events" - incidents so unacceptable that they should never happen - in just 12 months.
In a speech at University College London Hospitals, Mr Hunt suggested the UK has become "so numbed to the inevitability of patient harm that we accept the unacceptable" and called for a change in culture that means errors and injuries from care are constantly revealed and reduced.
International studies suggest there is likely to be significant under-reporting of "never events", according to health officials. Of those recorded in 2011/12, 70 patients were given "wrong site" surgery, where the wrong part of the body or even the wrong patient was operated on, and 41 people were given incorrect implants or prostheses.
"This is the silent scandal of our NHS", Mr Hunt said.
Norman Williams, president of the Royal College of Surgeons, described the figures as "horrendous" and said the Health Secretary was "quite right" to highlight the issue. He went on: "I think we are all duty bound to try to prevent this from happening and up our game so that these devastating mistakes won't occur."
Mr Hunt said: "We have allowed ourselves to settle for levels of patient harm that are simply unacceptable. The facts are clear - last year there were nearly half a million incidents that led to patients being harmed, and 3,000 people lost their lives while in the care of the NHS."
He added: "It is time for a major rethink - a different kind of culture and leadership, where staff are supported to do what their instincts and commitment to patients tell them.
"We must make sure that patients know where the buck stops and who is ultimately responsible for their care. And above all, we must listen more to NHS staff, so we can design systems that encourage them to act safely whatever pressures they face. I want the NHS to be the world's safest health system. It has all of the tools to do this, and I believe it should aspire to nothing less."
The speech came after revelations on Thursday that the health watchdog's cover-up over a failure to investigate a series of deaths stretched all the way to the top of the organisation. The Care Quality Commission's former chief executive, Cynthia Bower, was present during a discussion of the deletion of an internal review which criticised the regulator's inspections of University Hospitals of Morecambe Bay NHS Foundation Trust, where a number of mothers and babies died, according to an independent review.