Cumulina, who was created in the laboratories of the University of Hawaii Medical School, died in her sleep from natural causes.
She had reached the age of two years and seven months - about seven months above the average for a mouse. Her age corresponds roughly to human age of 95.
The effect of cloning on the ageing process has been a topic of intense interest to scientists. Recent data from cattle suggest cloning made them biologically younger and could extend their lifespan.
Little cloud
The rodent made headlines around the world in 1998 when her birth was reported in the journal Nature. Cumulina - Latin for "Little Cloud" - got her name from the cells that were used to make her.
The researchers, Dr Ryuzo Yanagimachi, Dr Teruhiko Wakayama and others, took genetic material from the nuclei of cumulus cells. These are tiny clouds of support cells that surround and nourish a developing egg in the ovaries of an adult mice.
This genetic material was injected into an "empty" mouse egg. The egg was then cultured for several hours before being transplanted into the womb of a surrogate mother.
Most of the early Hawaii embryos died, but about 3% survived. Some of these, including Cumulina, were mated with male mice and produced normal offspring. Others were cloned and their offspring cloned again and again.
When Dr Yanagimachi finally announced the breakthrough, the research team had 50 mouse clones.
Good mother
Cumulina raised two litters before "retiring," and lab personnel say she was a good mother. About eight months ago, Cumulina developed a skin tumour - common in ageing mice - and the tumour was successfully removed.
She had otherwise been healthy and active all her life, except for several days before her death.
Dr Yanagimachi has indicated that Cumulina's remains will be preserved and mounted in a new permanent exhibit in a new Institute for Biogenesis Research.