Simmonds is one of British para sport’s most recognisable athletes after bursting on to the scene in Beijing before going on to win eight medals including five golds across three Games before Tokyo.
She carried the flag for Great Britain at the opening ceremony alongside John Stubbs.
Simmonds previously finished fourth in the SB6 100m breaststroke and fifth in the SM6 200m individual medley, with 19-year-old teammate Maisie Summers-Newton claiming each of those titles.
Her final race, the S6 400m freestyle final, saw her disqualified before her fifth-placed finish was reinstated on appeal.
China’s Yuyan Jiang won in a new world-record time with Simmonds’ fellow Brits Summers-Newton fourth and Grace Harvey sixth.
There remains a chance Simmonds competes at the Commonwealth Games in Birmingham next year but her Paralympic career now appears to be over.
“I think that is my last competition,” she said after the race. “To go to four Paralympic games, including a home games and to come away with eight Paralympic medals and being part of that Paralympic movement as well. So I think for me, yes, this is going to be my last but I will go home and evaluate.
“I’m not just saying that because I’m gutted or anything like that, I knew going into these Games this was going to be the last and I don’t think I could go for another three years. I’m leaving it at the right time, I love it, I’ve absolutely had a wonderful competition and I’ve loved every minute of it.
“I can’t thank everyone enough for the support, my coach, my parents, my family, everyone, for getting me to these Games and the other four Paralympics which is amazing. There’s no words to describe it. I love the Paralympics and I love everyone on the team, it’s just been incredible but I’m looking forward to going home.
“Not having your family here in the crowd has been hard, for me they’re like my comfort blanket, even though I’ve been going for so many years.”
News of Simmonds’ likely retirement came ahead of three GB medals at Tokyo Aquatics Centre, including a fifth career gold for Bethany Firth.
Northern Ireland swimmer Firth retained her S14 100m backstroke crown in a time of 1:05.92, with team-mate Jessica-Jane Applegate taking bronze, just over two seconds behind.
Firth, 25, has now won the event at three successive Games, moving her on to a total of eight Paralympic medals, having also picked up two silvers in Japan.
Meanwhile, Reece Dunn collected the fourth medal of his debut Games, adding S14 100m backstroke bronze to freestyle and individual medley golds and butterfly silver.
The 25-year-old touched the wall in 59.97, with compatriot Jordan Catchpole 3.23secs slower in fourth.
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