Fra Bartolommeo painted this work in 1509, immediately following his return to Florence from Venice. In a scene of calm grandeur, the Holy Family is shown resting on their flight into Egypt under a date palm and pomegranate tree, while the Infant Saint John the Baptist presents a reed cross to the Christ Child, seated on the Madonna's lap. Saint Joseph leans on the donkey’s pack saddle, calmly observing the meeting of Christ and Saint John. A pomegranate, symbolic of Christ’s resurrection, lies half eaten in the foreground. The palm tree on the left is another symbol of the Passion, representing the palm fronds that would pave the road on Christ's final entry into Jerusalem.

Fra Bartolommeo constructed an evocative landscape which harmoniously combines the different stages of the narrative. In the distance on the right, the Holy Family are shown fleeing Bethlehem on a donkey, escaping King Herod’s massacre of the innocents. The landscape also includes a ruined arch, which alludes to the coming of Christ and the downfall of the Roman Empire's pagan order, personified by the Virgin. Although the Gospels relate that Christ and Saint John the Baptist first met as adults when the saint baptized Christ, Fra Bartolommeo here draws from New Testament apocrypha which describe the early life of Christ and were popular sources of inspiration for artists of this period.

The artist creates a remarkable tension between the Madonna and two children, both spatially and emotionally. They form a triangular shape, accentuated by the child Baptist’s outstretched left leg and the Madonna's extended right leg, the foot of which points outward. Fra Bartolommeo captured the Florentine ideal of beauty in the Madonna’s graceful pose and softly modelled face and neck, which is further enhanced by her placement in a pristine landscape, an aspect of religious painting to which the artist made a unique contribution.