The men, aged 21 and 25, are in custody after being arrested on suspicion of causing unnecessary suffering to a protected animal.
South Wales Police and the RSPCA were called to Westgate Street at about 7pm on Saturday after the horse was found collapsed outside the Principality Stadium.
A video shared on Twitter shows the horse lying on the ground as three women attempt to bring it to its feet.
The horse was eventually able to stand up after having laid on the floor for almost three hours and was taken to the Whispering Willows Sanctuary in Pontardawe and Gowerton, South Wales.
— Shirley P Wilson (@ShirleyPWilson)April 20, 2019
Shaun Fox, from the sanctuary, said the horse was “exhausted and suffering from heatstroke which could have been fatal”.
By Sunday morning, Mr Fox said the horse was “doing OK” and could eat hay and drink water.
Staff at the sanctuary, who believe the horse is pregnant and between 3 and 4 years old, are waiting for a vet to assess her.
Jeanette Cook, a former veterinary nurse who attended to the horse before the sanctuary staff arrived, said the horse was in an “awful state” and looked “exhausted”.
“Someone had thrown a bucket of water over her, but I told them not to do that because it was so hot it can send the animal into shock,” she said.
“We tried to rub the pony’s feet to get the blood circulating, but it took four goes till we could lift her to standing.
“She was sweating and panting fast, and I had to hold my hand under her head to stop it hitting on the pavement.
“She was in foal and looked very young, but her owner was running her around Cardiff.“
A police spokeswoman said: “South Wales Police responded to numerous calls reporting concern for the welfare of a horse on Westgate Street, Cardiff, shortly before 7pm last night.
“On arrival, officers found the animal collapsed on the street.
“Alongside members of the public, the officers tended to the horse while making contact with Whispering Willows Sanctuary, who subsequently arrived and took over care of the horse.
“Two men, aged 21 and 25, were arrested at the scene on suspicion of causing unnecessary suffering to a protected animal. Both are currently in custody.”