A two-year-old black and white cat named Patch died following a suspected poisoning in Bro Dulas, Llanidloes.
Two other cats in the area were also put to sleep after they became unwell.
RSPCA chief inspector Phil Lewis said: "We don't know whether these incidents were accidental or deliberate or who may have done it."
Patch's owner said: "I am just so angry and devastated. Patch was such a quiet and loving cat."
Mr Lewis added: "We're calling on all cat owners in the Llanidloes area to be vigilant and to take their cat to a vet straight away if they suspect they have been poisoned."
Potential signs of poisoning could include vomiting, difficulty breathing, increased thirst, and appearing to be be sleepy and uncoordinated.
The RSPCA is urging cat owners to be vigilant after suspected cat poisoning deaths in Powys.