With his friend and colleague, Arthur Surridge Hunt, he took part in the archaeological dig of Oxyrhynchus and discovered many ancient manuscripts known as the Oxyrhynchus Papyri, including some of the oldest known copies of the New Testament and the Septuagint. Other notable finds are extensive, including previously unknown works by known classical authors. The majority of the find consists of thousands of documentary texts. Parabiblical material, such as copies of the "Logia (words) of Jesus" were also found.
In 1895, Grenfell and Hunt were the first archaeologically to explore the site of Karanis (present Kom Aushim) in Fayum.
In 1908, he became Professor of Papyrology at Oxford and was part of the editing team of The Oxyrynchus Papyri and other similar works.