As Thompson was bidding an emotional farewell, Australia's Brooke Hanson was celebrating the greatest individual performance at this event with six gold medals.
Aaron Peirsol also made his mark on the final day when he capped off the meet with two world records.
The most decorated swimmer in history with 83 international medals, including eight golds from four Olympic Games, Thompson wrote the final line in her brilliant career by taking bronze in the 100m butterfly.
The swim brought the 31-year-old American's career full-circle, Thompson having made her competitive international debut in Indianapolis at the 1987 Pan Am Games where she shot to prominence capturing two golds and a bronze.
Seventeen years later, Thompson showed she still has what it takes to reach the podium, winning two golds, a silver and a bronze in her final competitive swim before heading back to medical school.
"The medals and the records aren't what's important to me but I guess it's a nice way to go out," said Thompson, who is scheduled to start her pediatric rotation at Columbia University hospital on Tuesday.
"It was just great to be part of the U.S. team one last time and end my career where it all started.
"I'm ready to be done."
Hanson, however, appears to be just getting started.
The 26-year-old Australian cemented her place among the sport's greats, storming to victory in the 200m breaststroke to become the first competitor to capture six gold medals at a single short course world championships.
A gold and silver medallist in Athens, Hanson brought her Olympic form to Indianapolis, winning a record five individual events and helping Australia to victory in the 4x100m medley relay.
The results put Hanson in exclusive company joining Mark Spitz, Kristin Otto, Ian Thorpe and Michael Phelps as the only swimmers to win as many as six golds at an Olympic or world championships.
"I just went out there and wanted to show the world that I wanted to be counted," said Hanson, who twice failed to make the Australian Olympic team. "I wanted to create history tonight.
"What I achieved this week is amazing. It hasn't sunk in yet and I don't think it's going to."
Britain's James Hickman also added his name to record books with his victory in the 200m butterfly, becoming the first to win gold in the same event at five different world championships.
Hickman first claimed the title at the 1997 championships in Sweden and followed up with successful defenses in 1999, 2000 and 2002.
Peirsol provided the crowd with the big finish it wanted, lowering his own world record in the 200m breaststroke to one minute, 50.52 seconds then helping the U.S. 4x100m medley relay team to another world record of 3:25.09 to conclude the meeting.
"I wanted to swim here and do the best I could and I think I did that," Peirsol said.
"Going into this I had a pretty good inclination that I could do something like that."
Peirsol's efforts contributed to a dominating meet by the U.S. which took gold in 21 of 40 events and finished with 41 medals overall.Australia finished a distant second with seven golds and 28 medals in total.