The 20-year-old had to settle for silver behind Ukraine’s Yelyzaveta Mereshko in the 400-metres freestyle S6, an event Simmonds had won at two Paralympics and two previous World Championships.
Simmonds was one of five British athletes to claim silver medals at Tollcross pool alongside her fellow West Midlands swimmer Tully Kearney, Scottish pair Andrew Mullen and Scott Quin, and City of Sheffield’s James Crisp.
There was a fifth British medal for Susie Rodgers, who collected a bronze.
Seven-times world champions Simmonds had recorded the fastest time in qualifying and went head to head with Mereshko until the final length of a two-horse race but finished eight-tenths of a second behind in five minutes, 22.54 seconds.
Simmonds said: “It was such a tough race. I did everything I needed to do, it was a good time, one of the best times I’ve done since 2012.
“I gave the best that I could on the day to be honest, which didn’t lead to a gold medal. But you can’t always get what you want.
“I’ve been the gold medalist since 2008 so it’s hard but I’m going to get ready for the 100 breaststroke and go out and enjoy it.”
Mullen set a new European record on his way to silver in the men’s 50m backstroke S5.
The Glasgow swimmer broke his own mark to finish in 37.29 in qualifying before swimming slightly slower in the final and two seconds behind the world record holder, Brazil’s Daniel Dias.
The 18-year-old, who has four more events this week, said: “I love racing in front of my friends and family, it’s great having them here to support me, and I’m just glad I can bring them back a silver medal.
“I was really happy with the swim. It was slower than this morning, but I can’t complain…it’s still one of the fastest swims I have done. I can’t complain with a PB and a silver medal.
“Daniel is obviously a really fast guy. I don’t tend to focus on what he’s doing, I just focus on my times and chipping away at my PB. I’m just happy to keep progressing.”
Edinburgh swimmer Quin, 25, claimed silver in the men’s 100m breaststroke behind Marc Evers of Holland.
Crisp began his sixth World Championships with a season’s best of 1:04.43 to finish the fastest qualifier in his favoured 100m backstroke S9.
That time would easily have been enough to claim gold in the evening but the 32-year-old recorded 1:05.12 to finish just behind Australia’s Brenden Hall.
Kearney, from Boldmere Swimming Club in Sutton Coldfield, set a new personal best of 1:10.52 in the 100m backstroke, but the 18-year-old was almost two seconds behind Australia’s Ellie Cole, who set a new world record.
Beckenham-based Rodgers added to the five medals she won two years ago when she claimed bronze in the women’s 100m freestyle S7.
Ireland’s Darragh McDonald, the reigning world and Paralympic champion, had to settle for bronze in the 400m freestyle S6.
In the early session, 16-year-old Bournemouth College student Alice Tai broke her own British record in the 50m freestyle S10 with a swim of 29.60 but missed out on a final place.