There are calls for an alternative to school contact groups isolating for 14 days after a classmate tests positive.
Some parents say their children have isolated three times in the past three months - and that it is detrimental to their wellbeing.
A petition to the Senedd also says working parents are suffering, with employers not always sympathetic if they have to stay home with children.
The Welsh Government said it was working hard on testing developments.
"We are sorry to hear about these experiences," a Welsh Government spokeswoman said.
"We are learning more about the virus all the time and experts from across the UK regularly review the self-isolation guidance to make sure the length of time is right to stop it being passed on to other people."
Schools generally keep the same bubble or group of children together to reduce the number that has to isolate if a pupil tests positive for coronavirus - but parents say these groups can end up being large.
Kate Bradley, from Newport, said her son in Year 9 had just finished a period of isolation and, after one day back at school, had been told to isolate again.
Ms Bradley said: "He had felt so anxious about going back and now I feel dreadful for telling him it would all be fine, and it wasn't.
"He had one day back, and now it's another two weeks of no sports, no socialising, no going outside."
And her daughter, in Year 7, having dealt with starting secondary school after months off in the first lockdown and missing all the build-up, has already had to isolate twice.
"My son is normally very positive about school and seeing his friends, but even he's reached the point where he's had enough of it hanging over his head.
"I can't praise the school enough, I think they've done absolutely everything that they can, it's a very Covid-secure school - it's the rules [that are the problem]."
Children are not able to leave the house at all for 14 days and cannot go out to exercise after potential contact with a positive case, under the current rules.
"We are big rule-followers, and the children just want to keep people safe. We've seen my mum once, outdoors, since August," Ms Bradley said.
"But self-isolation is worse than lockdown because at least then you could go out for a walk or a bike ride, but this is just in the house and there is nothing to do, it's like a prison sentence.
"My son noticed how unfit so many children were when he went back to play football after the first lockdown so it's not so much about learning, the home learning our school has offered has been excellent, it's about exercise, social interaction."
'There has to be a safe answer'
Ms Bradley said she did not wish to criticise any school, but she believed there must be a safe alternative.
"I don't think there are many adults who have had to self-isolate in the way these children are, you wouldn't expect any adult to [spend] eight weeks out of the last 12 isolating, so there has to be a safe answer and we owe it to our children to find it."
The author of the petition, Victoria Codling, who also has children at a school in Newport, believed a negative test after five days of isolating could be a solution - as is the case in England for people arriving in the country from abroad.
According to Ms Codling's petition, which has received more than 800 signatures: "Isolating for 14 days is so detrimental to their mental and physical wellbeing, it is disproportionate to the risk of their exposure to coronavirus in the first place.
"Some children are enduring their third period of isolation in as many months. Children with additional needs or from disadvantaged backgrounds are even more adversely affected.
"Working (non-isolating) parents are suffering with employers not always sympathetic in these tough economic times."
There are also concerns from supporters of the petition over the workload of teachers having to simultaneously teach children in school and those isolating and learning online.
What if pupils are told to isolate over Christmas?
Ms Codling told BBC News she had heard of young children staying in their bedrooms with no human contact, having food brought to them.
She added that people were terrified of being asked to isolate towards the end of term - meaning they would have to do so over Christmas.
"I dread to think how much school has been missed," she said.
Ms Codling added that, while some schools were sending home small groups of pupils who have had contact, others were asking entire year groups to self-isolate.
"They can't run, they can't exercise, some are staying in one room of the house having food brought to them when they don't have any symptoms.
"But then their parents and siblings don't have to isolate at all, parents are confused - it is confusing.
"Some children will cope fine with distance-learning and talking to their friends on Zoom but some don't understand the change in their routine and just don't cope - it's their normality, it's not just about education but social and emotional development."
The Welsh Government added: "Testing technology is developing all the time and we are working hard to make sure that these new developments are available for use as soon as possible in Wales.
"We know the pandemic has had a huge impact on everyone, but especially on children and young people.
"Support is available if people need it - this includes through our CALL mental health helpline and the Young Persons Mental Health Toolkit."