I think both George and Cindy (and Lee) knew that something was wrong as soon as the car was found at Amscot. When Cindy picked Casey up at TL's apartment, I think she still believed Caylee was with the nanny. Later that evening when she first heard Casey's story about the nanny kidnapping Caylee, Cindy reacted by immediately calling 911, frantic to get help. At this point, I think Cindy believed Casey's story.
The next day, July 16, 2008, the police had Casey accompany them to the Sawgrass Apartments and then to the Universal Studios where Casey said she worked. It was there that Casey admitted that she didn't work at Universal Studios, and LE uncovered many lies in her story (the apartment at Sawgrass empty since Feb; no ZFG matching Casey's description; the friends she said she worked with that knew ZFG, didn't exist; etc). After LE tried to get the truth from her and she refused, she was arrested for obstruction of justice, child endangerment, and lying to police.
In one of the local media stories at the time, Cindy related that she, George, and George's sister, were monitoring the television at home expecting an Amber Alert to be issued. Cindy said they received a phone call from a friend saying, "quick turn the channel to such and such a channel, Casey's been arrested."
I think it was at that point, when they learned that Casey had been arrested, and that the police had uncovered so many lies in Casey's story, that they realized that Caylee was gone and likely deceased.
July 16, 2008 was a Wednesday. By Friday, July 18th, George and Cindy were in full cover up mode. They did an interview in their home with a local news media. In that interview they stressed the child safety in thier home - the pool ladder always being put away when not in use, the shed always being locked and only George and Cindy having keys, Casey regularly using a shovel to dig up bamboo in the back yard so Caylee wouldn't hurt her feet stepping on the shoots. These were things that would later become significant - the pool ladder, the shed, and the shovel, and they had explanations for each in advance.
So, I think it was the day after finding the car at Amscot and finding Casey at TL's apartment, that George and Cindy came to realize that Casey had lied and Caylee was gone. I think they knew then that Casey had killed Caylee.