Both Florida and Alabama instituted mandatory evacuations to thousands of people due to the storm.
In Florida, those evacuations included coastal communities in direct aim of the powerful storm. Senator Rick Scott encouraged residents in designated areas to evacuate as soon as possible, as he warned in a social media post: "DO NOT WAIT! Get out NOW!"
Governor of Alabama Kay Ivey issued a mandatory evacuation for all non-residents, tourists and visitors in key counties likely to be heavily affected by the storm.
On Saturday, Homeland Security Secretary Markwayne Mullin said the US president had approved emergency declarations for the two states to "ensure federal resources are available" for support.
Hurricane Isaias is the first hurricane in the Atlantic's hurricane season, which largely has been delayed due to El NiƱo conditions in the Pacific.
It marks the first time in more than 30 years that a hurricane did not form before October.
Ahead of the storm, the National Hurricane Center (NHC) warned it was likely to bring "life-threatening storm surge" to the US Gulf Coast.
All warnings pertaining to Isaias had been discontinued on Saturday morning, the NHC said.
The post-tropical cyclone is currently moving north and is expected to cross Alabama and into the Tennessee Valley later on Saturday and Sunday, according to the National Weather Service.
Hurricane-force winds on Friday evening extended outward up to 35 miles (55 km) from Isaias' centre, and tropical storm-force winds extended as far as 205 miles (335 km).
Two other storms are also forecast to batter North America this weekend.
Hurricane Simon is bearing down on the Pacific coast of Mexico as a category one hurricane. It is set to pick up speed and become category four by Saturday, eventually making landfall near Puerto Vallarta on Sunday, according to Reuters.
Further north, Tropical Storm Rachel, a downgraded hurricane, is heading toward landfall around the US-Mexico border, along the Pacific.
While, Rachel is expected to reach the coast late on Saturday, the impact of the storm is already being felt due to high tides in southern California.
Video footage and photos show several streets under water in Newport Beach, California, through a combination of the tropical storm swells at sea and high tide.
Posting on its account on X, the City of Newport Beach advised people to "avoid the Balboa Peninsula due to street flooding caused by recent storm conditions and elevated tides".
It also urged people not to drive through flooded streets. Bulldozers have been shoring up the beach to try and prevent further flooding.
With additional reporting by Simon King and Matt Taylor, BBC Weather