The tornado first touched down at 3:05 p.m. CDT (2005 UTC) southwest of Hamilton, Alabama, before quickly becoming violent and reaching EF5 intensity as it approached and struck Hackleburg, destroying a large portion of the town.

[2] An area of low pressure consolidated over Texas on April 26 and traveled east while the aforementioned shortwave trough traversed the Mississippi and Ohio River valleys.

Multiple episodes of tornadic activity ensued with two waves of mesoscale convective systems in the morning hours followed by a widespread outbreak of supercells from Mississippi to North Carolina during the afternoon into the evening.

[2] Tornadic activity on April 27 was precipitated by a 995 mbar (hPa; 29.39 inHg) surface low situated over Kentucky and a deep, negatively tilted (aligned northwest to southeast) trough over Arkansas and Louisiana.

A strong southwesterly surface jet intersected these systems at a 60° angle, an ageostrophic flow that led to storm-relative helicity values in excess of 500 m2s−2—indicative of extreme wind shear and a very high potential for rotating updrafts within supercells.

Ample moisture from the Gulf of Mexico was brought north across the Deep South, leading to daytime high temperatures of 77 to 81 °F (25 to 27 °C) and dewpoints of 66 to 72 °F (19 to 22 °C).

[2] The tornado initially touched down in Marion County, Alabama about 5 miles (8.0 km) west-southwest of Hamilton around 3:05 p.m. CDT and tracked to the northeast, causing significant tree and roof damage.

[6] The tornado would claim its first life as it moved over Highway 43 a second time, striking a vehicle and killing the occupant, Bridgett Cantrell.

[7] As it approached Hackleburg, moving parallel to US 43, the tornado further strengthened to EF5 intensity and widened to 0.75 miles (1.21 km), sweeping away numerous homes along the highway.

[10] The tornado would move over populated areas as it entered into the southwestern side of Hackleburg, where a man would be killed after refusing to take cover in a storm shelter.

[15][16] The tornado maintained EF5 strength as it struck a Piggly Wiggly grocery store, a shopping center, and a Wrangler Jeans plant, tossing cars as far as 200 yards (180 m) from where they originated.

[18] The tornado completely debarked numerous trees in town, and even tore up poured concrete from the ground at one location.

The presence of well-built homes swept away, extensive wind-rowing, and cars thrown hundreds of yards were the main factors that led to the EF5 rating in Hackleburg.

The tornado damaged 495 structures along a 25.14-mile (40.46 km) path,[23] resulting in monetary losses upwards of $160 million (2021 USD).

[25] At 3:28 p.m. CDT, the tornado crossed into Franklin County, moving to the northeast at an estimated forward speed of 69 miles per hour (111 km/h) while having a maximum width of 2,125 yards (1,943 m).

After passing through approximately three miles of vegetation and trees, the tornado crossed Woodward Road, located to the southwest of Phil Campbell.

The tornado ripped the roof off of another concrete storm shelter as it entered into Phil Campbell, where twenty-one people would be killed.

A 25-foot (7.6 m) section of pavement was scoured from a road in Phil Campbell, with chunks of asphalt scattered up to 1⁄3 mile (0.54 km) away, and numerous trees were completely denuded and debarked, one of which had a car wrapped around it.

[27][19]EF4 and EF5 damage continued as the tornado exited Phil Campbell and tore through rural areas, sweeping away additional homes as it roughly followed County Roads 81 and 82.

[28] The tornado continued into Lawrence County and maintained EF5 strength as it struck the small town of Mount Hope, where significant devastation was incurred to single-family homes and a restaurant.

[27] WAAY-TV meteorologist and Mount Hope resident Gary Dobbs spotted the tornado from his front window but was unable to get to his storm shelter because he was giving a live report to viewers of WAAY.

[27] The tornado continued northeast at EF3 strength as it struck Langtown, where multiple homes lost their roofs or had only interior walls left standing, and a gas station and a store sustained significant damage.

The tornado then weakened significantly, twisting irrigation equipment and producing only intermittent EF0 tree damage southwest of Hazel Green and through rural areas.

[17][27] In all, hundreds of homes received moderate to major damage along the path from Limestone to Madison County with many of these being total losses, and thirteen people were killed.