Levofloxacin is a third-generation fluoroquinolone, being one of the isomers of ofloxacin, which was a broader-spectrum conformationally locked analog of norfloxacin; both ofloxacin and levofloxaxin were synthesized and developed by scientists at Daiichi Seiyaku. The Daiichi scientists knew that ofloxacin was racemic, but tried unsuccessfully to separate the two isomers; in 1985 they succeeded in separately synthesizing the pure levo form and showed that it was less toxic and more potent than the other form.
It was first approved for marketing in Japan in 1993, for oral administration, and Daiichi marketed it there under the brand name Cravit. Daiichi, working with Johnson & Johnson as it had with ofloxacin, obtained FDA approval in 1996 under the brand name Levaquin to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia, uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.
Levofloxacin is marketed by Sanofi-Aventis under a license agreement signed with Daiichi in 1993, under the brand name "Tavanic".
Levofloxacin had reached blockbuster status by this time; combined worldwide sales of levofloxacin and ofloxacin for J&J alone were  in 2009.
The term of the levofloxacin United States patent was extended by the U.S. Patent and Trademark Office 810 days under the provisions of the Hatch Waxman Amendment so that the patent would expire in 2010 instead of 2008. This extension was challenged by generic drug manufacturer Lupin Pharmaceuticals, which did not challenge the validity of the patent, but only the validity of the patent extension, arguing that the patent did not cover a "product" and so Hatch-Waxman was not available for extensions. The federal patent court ruled in favor of J&J and Daiichi, and generic versions of levofloxacin did not enter the U.S. market until 2009.