The village was situated on flat terrain on the central coastal plain. Two roads connected the village to a network of highways that led to Jaffa, Lydda, and Ramla. A secondary railway line connected Kafr 'Ana with the main line running south of the village between Lydda and Tulkarm. Kafr 'Ana may have been built on the site of the Canaanite village of Ono, which was mentioned in the Karnak List of Thutmose III (fifteenth century B.C.). It appears to have been a fortified town in the Iron Age (I Chronicles 8:12), some three centuries later. In the Byzantine period it was known as Onous. In 1596, Kafr 'Ana was a village in the nahiya of Jerusalem (liwa' of Jerusalem) with a population of 116. It paid taxes on a number of crops, including wheat, barley, olives, and fruits, as well as on other types of property, such as goats, beehives, and vineyards.
In the late nineteenth century, Kafr 'Ana was a village built of adobe bricks and surrounded by palm trees. The houses of the modern village of Kafr 'Ana were built along the above-mentioned pair of roads; as newer houses were constructed, the village expanded westward and northward toward the Jaffa–Lydda road. The population at that time was entirely Muslim. The village had two schools, one for boys and another for girls. The boys' school, founded in 1920, owned 22 dunums of land; 270 students were enrolled in 1944. The girls' school was established in 1945; 57 students were enrolled that year. The residents grew crops and raised poultry and bees. In 1944/45 a total of 2,214 dunums was devoted to citrus and bananas and 11,022 dunums were allotted to cereals; 597 dunums were irrigated or used for orchards. The village itself was an archaeological site, and next to it, to the east, lay another archaeological site: Khirbat Kafrajun (138159).
Kafr 'Ana was one of a cluster of villages east of Jaffa that was occupied during the Haganah's Operation Hametz (see Bayt Dajan, Jaffa sub-disctrict). This offensive was designed to isolate Jaffa and make it possible for the Haganah to conquer the city. It was carried out by units from three Haganah brigades, who began the assault four days after the Irgun Zvai Leumi (IZL) had launched a frontal attack against Jaffa itself. Kafr 'Ana was probably seized at the same time as the neighboring village of Saqiya, which was occupied by the Alexandroni Brigade on 29 April.
Some four months later, on 13 September, Kafr 'Ana was one of fourteen villages slated for destruction by Israeli prime minister David Ben-Gurion, who asked the cabinet for formal permission. Morris does not make clear whether permission was granted, but notes that the villages were levelled soon afterwards. Later that month, Kafr 'Ana was mentioned as a site for the settlement of new Jewish immigrants.
Yagel (138155) was established on village lands in 1950, south of the village site; Newe Efrayim (138159) was established in 1953, on or very near the village site.
Part of the site is a vacant lot. On other parts, olive trees grow, along with cypress and eucalyptus trees that have been planted by the residents of the Israeli settlements. No traces of the old houses can be discerned. Apartment buildings and a small park have been built on the surrounding land.