The quiescent spell was broken by a series of major tornado outbreaks beginning with the Yazoo City Mississippi Outbreak on 24 April 2010. The EF-4 tornado that hit Yazoo City was over 1.5 miles wide and had an uninterrupted 149 mile damage path. The entire outbreak of 51 tornadoes included 6 EF3 and 3 EF4 twisters, and resulted in 10 fatalities and almost 200 injuries. Another major tornado outbreak was focused over central Oklahoma on the afternoon of 10 May. More than 35 tornadoes, including 4 EF3 and 2 EF4, touched down over the area causing 3 fatalities and 115 injuries. One of the EF4 tornadoes on this day initially touched down a few hundred yards east of the National Weather Center in Norman, Oklahoma.
The month of June was highlighted by a major tornado outbreak on 5 June over Illinois, Indiana and Ohio, with an EF4 tornado striking the town of Millbury near Toledo, Ohio resulting in 7 fatalities. Powerful tornadoes struck Minnesota and Wisconsin on the evening of 17 June, with 3 fatalities associated with three separate strong-to-violent tornadoes.
Killer tornadoes struck both Montana and North Dakota during mid summer, before an unusually strong September storm struck the New York City area on 16 September. In another unusual event, 11 tornadoes were reported over Arizona and Utah on 6 October with significant damage in the town of Bellemont, Arizona from multiple tornadoes during the early morning hours. Finally, an extratropical cyclone of record breaking intensity, spawned an extensive wind and tornado outbreak over the central United States on 26 October, with 53 tornado reports and over 300 reports of damaging wind.