The tornado tracked eastward through Joplin, and then continued across Interstate 44 into rural portions of Jasper and Newton counties, weakening before it eventually dissipated at 6:28 p.m. CDT (UTC–05:00), lasting just over 45 minutes on the ground.

[17] By 8:00 a.m. CDT (1300 UTC) on May 22, forecasters at the SPC realized that a more intense weather outbreak was likely to occur, and upgraded a large swath of the Midwest to a moderate risk.

[16]: 17 The tornado first touched down in Newton County, Missouri, just east of the Missouri–Kansas state line, approximately one-half mile (0.80 km) southwest of the intersection of South Central City Road and 32nd Street, at 5:34 p.m. CDT (22:34 UTC).

[20] Civil defense sirens sounded in Joplin twenty minutes before the tornado struck, in response to the tornado warning issued at 5:17 p.m. CDT (22:17 UTC) for northwestern Newton and southwestern Jasper counties in Missouri, and southeastern portions of Cherokee County, Kansas, but many Joplin residents did not heed the warning or the sirens.

[21][22] The tornado moved east-northeast and strengthened to EF1 intensity as it continued through rural areas towards Joplin, snapping trees and power poles and damaging outbuildings.

A large steel-reinforced step and floor structure leading to a completely destroyed medical building was "deflected upward several inches and cracked".

[24] Damage became remarkably widespread and catastrophic at and around the nearby St. John's Regional Medical Center, which lost nearly every window on three sides, interior walls, ceilings, and part of its roof; its life flight helicopter was also blown away and destroyed.

[20] Vehicles in the hospital parking lot were thrown into the air and mangled beyond recognition, including a semi-truck that was tossed 125 yards (114 m) and wrapped completely around a debarked tree.

[26] Small pieces of debris from the hospital, including X-rays, medical reports, and dental records, were found in Greene and Polk counties many miles to the east.

[29] No one was in the high school at the time, as the graduation ceremonies held about three miles (4.8 km) to the north at Missouri Southern State University had concluded shortly before the storm.

As the tornado crossed Connecticut Avenue further to the east, it destroyed several large apartment buildings which resulted in 14 fatalities, along with a Dillons grocery store, and a bank.

The tornado then approached Rangeline Road, the main commercial strip in the eastern part of Joplin, affecting additional neighborhoods along 20th Street.

As the tornado struck a Pizza Hut on South Range Line Road, store manager Christopher Lucas herded four employees and 15 customers into a walk-in freezer.

An Academy Sports + Outdoors store along Range Line sustained major structural damage, and a chair was found impaled legs-first through an exterior stucco wall there.

The last area of EF5 damage occurred in the industrial park, and a nearby Fastrip gas station and convenience store was completely destroyed.

Joplin officials after the tornado announced plans to require hurricane ties or other fasteners between the houses and their foundations (devices add about US$600 to the construction costs).

[62] In 2013, the American Society of Civil Engineers published a study disputing the tornado's initial EF5 rating, based on surveying damage on over 150 structures within a six-mile segment of the storm's path.

Bill Colbourne, a member of the engineering team that surveyed the damage, declared that "a relatively large number of buildings could have survived in Joplin if they had been built to sustain hurricane winds."

Then Governor Jay Nixon declared a state of emergency for the Joplin area shortly after the tornado hit, and ordered Missouri National Guard troops to the city.

[38] By May 23, Missouri Task Force One (consisting of 85 personnel, four dogs, and heavy equipment) arrived and began searching for missing persons.

This led Federal Emergency Management Agency Administrator Craig Fugate to develop the concept of the Waffle House Index for measuring disaster impact.

In May 2012, the Missouri National Guard released documents showing that four soldiers looted consumer electronics from a ruined Walmart during efforts to locate survivors the day after the tornado.

[72]The Joplin tornado generated an estimated 3 million cubic yards of debris,[73] an amount sufficient to cover a football field 120 stories high.

[36]: 19  Removal efforts lasted for months, and at their height more than 410 trucks a day transported debris to landfills in Joplin itself, as well as nearby Galena and Lamar.

[78] President Barack Obama toured the community on May 29, flying into Joplin Regional Airport and speaking at a memorial at the Taylor Performing Arts Center at Missouri Southern State University about two miles (3.2 km) north of the worst of the devastation.

[83] The city, warned by federal officials that it should expect to lose 25% of its population following the tornado, responded quickly and built an average of five houses a week between 2011 and 2022.

Home Depot officials disagreed with the study published by The Kansas City Star and said they would use the tilt-up practice when they rebuilt the Joplin store.

[87] Within two years, the city's workers and community groups compiled and published "Joplin Pays it Forward" to give recovery advice to other places struck by disasters.

[89] Eighteen people committed suicide in the wake of the tornado, according to the executive director of the Community Clinic of Southwest Missouri, a co-chair of the city's long-term recovery team.

These include Heartland: A Portrait of Survival, directed by Erica Tremblay and featured at the Omaha Film Festival and the St. Louis International Film Festival,[91][92] as well as Deadline in Disaster (directed by Beth Pike), which followed the staff of The Joplin Globe in the tornado's aftermath and received a regional Emmy in the Documentary-Cultural category during the 37th Mid-America Emmy Awards.