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In 1985, Mecklenburg assumed the role of president, CEO, and director for Northwestern Memorial Corporation and Northwestern Memorial Hospital. Under his guidance, Northwestern Memorial Hospital became a recognized leader in Chicago health care: by 2000 it had achieved a 30 percent reduction in cost per case and an 18 percent market share, the highest in its service area, while also increasing patient admittance and satisfaction levels.

Mecklenburg spearheaded the replacement of Northwestern Memorial Hospital's medical center with a new, state-of-the-art facility in downtown Chicago, widely considered to be the most ambitious hospital construction project in the country in recent history. Mecklenburg has been chairman of the board at the Illinois Hospital and Healthsystems Association and the American Hospital Association.