The distance queen joined Simone Manuel, Ryan Murphy, and Michael Andrew as the big winners on a thrilling final night in San Antonio.
Five-time Olympic gold medallist Ledecky led the 800m free from start to finish to touch home in 8:13:64, 12 seconds clear of her nearest rival Leah Smith.
Ledecky, who also won the 200m, 400m and 1500m free, said, “I was happy to end on a pretty good note in the 800. I think there’s a lot to take away from the first time competing again in this kind of setting.
"It was just good practice to get on a plane and travel and to get back into that competition routine.”
In the men’s 800m free, Egypt's Marwan Elkamash recorded a time of 7:58.33 to claim the fifth Pro Series win of his career.
Olympic champion Simone Manuel took the 50m free crown in 24.70s, to go with her 100m free victory earlier in the week.
"I would've liked to swim faster. I'm always going to think that," she said. "I had some goal times I wanted to hit at this meet that I didn't hit. I haven't been to a meet during COVID and that's a different experience."
Rio 2016 medley relay gold medallist Olivia Smoliga overcame a stacked women's 100m backstroke field - featuring six U.S. National Team members - to win in 59.49s.
World record holder Regan Smith (59.50s) was second with Olympic silver medallist Kathleen Baker third.
Defending Olympic champion Ryan Murphy continued his good form in Texas to win the 100m backstroke in 53.56.
Having won the 200m back a day previously, the 25-year-old completed a second backstroke sweep in his past three Pro Series competitions.
Next up, Annie Lazor and Nic Fink captured wins in 2:24.45 and 2:11.92 in the women's and men's 200m breaststroke respectively.
Madisyn Cox claimed the women’s 200m Individual Medley title in 2:10.84 while Michael Andrew finished over a second ahead of his rivals to win the men’s event in 1:58.05.
“The biggest thing we’re trying to work on is closing that last 50 with more speed,” Andrew explained. “I was at 30.0 this evening, and 29.6 this morning, so there’s some things we have to work on, some endurance, but overall I’m happy to go 1:58 and have a much better swim.”
Bidding to make a fifth Olympic team at age 36, Ryan Lochte finished fifth in the 200 individual medley.
The next TYR Pro Swim Series event will be in April 2021, with details to be released Monday, March 8.