Against his father's will he turned away from a career in the law and decided to study philosophy instead, a decision he would not have been able to make but for the patronage of Piero di Cosimo de' Medici.
In 1458 Landino replaced Cristoforo Marsuppini as the chair of rhetoric and poetry at the Florentine Studio.
His students, seeking a more renowned teacher, initially opposed Landino's appointment, but he nevertheless remained and became an important part of the cultural and intellectual life of Florence.
Of special importance to the Renaissance, Landino prepared commentaries on the Aeneid (1478) and The Divine Comedy (1481).
To promote the use of vernacular Italian, Landino held lectures on Petrarch and translated and published Pliny's Historia naturalis (1476) and Giovanni Simonetta's Latin life of Francesco Sforza (1490).