Lloyd Mifflin was born on September 15, 1846, in Columbia, Pennsylvania. His father, John Huston Mifflin, was English, and his mother, Ann Bethel Heise, was from German descent. His mother died when he was very young. Thus, Lloyd Mifflin's early childhood education, notably painting, came from his father, who had studied at The Pennsylvania Academy of Fine Arts. His formal education started at a nearby country school in Norwood. He later attended the Washington Classical Institute in Columbia. At the age of fourteen, he spent a majority of his time reading his favorite poets by the Susquehanna River with friends.

His father pushed him to think for himself and develop his own ideas. His father also taught him to paint. Mifflin studied in Philadelphia with Thomas Moran, who was his teacher and who eventually shared his love of mountains with Mifflin. They also examined J.M.W. Turner landscape paintings together. He also studied abroad. He traveled to Düsseldorf, Germany with the hope of studying painting with Professor Oswald Auchenbach of the Royal Academy. When Mifflin was unable to connect with Auchenbach, he learned from educator Herman Herzog. Paul A. W. Wallace, author of Lloyd Mifflin; Painter and Poet of the Susquehanna, quotes Mifflin in a letter back home on June 9, 1872: "I am at work in my studio, at rather rudimentary work too, under Herzog's supervision. I will go direct to nature with box and paint in a week, after working charcoal previously—and then will try to paint something that may be called a picture." The State Museum of Pennsylvania holds a large collection of Mifflin's paintings.

He eventually put the paint brushes down and turned to another love, poetry. The fumes of his paintings caused his transfer. He often read poems by Longfellow and Tennyson for inspiration. His first publication was called The Hills (1896), which was illustrated by Moran. The Hills was a collection of sixteen poems. At the Gates of Song: Sonnets (1897) was published quickly after The Hills. It has been said that Lloyd Mifflin wrote fifteen sonnets in a single day and could have written another five if he had a little more time. Mifflin never married so many assumed that his work was his love. In 1898, he published his next book of sonnets entitled The Slopes of Helicon, and Other Poems. Soon after, he wrote poems about Greek Mythology titled Echoes of Greek Idylls (1899), which was a collection of 85 sonnets. In the following nine years he published, The Fields of Dawn and Later Sonnets, Castalian Days, Lyrics, The Fleeing Nymph, and Other Verse, Collected Sonnets of Lloyd Mifflin, My Lady of Dream, Toward the Uplands: Later Poems, Flower and Thorn: Later Poems. Flower and Thorn: Later Poems is a collection of fifty sonnets, two of which are dedicated to fellow Pennsylvanian Robert Fulton. Fulton was an inventor in the later 1700s and early 1800s. Mifflin writes about Fulton:

Time honored son, whose memory we revere,

Around the wondering earth thy lustrous name

Shone in old days, a sudden star of Fame!

A copy of Flower and Thorn: Later Poems (1909)can be found at The Pennsylvania State University Library. In 1916, Mifflin published his last collection of poems entitled As Twilight Falls.

There were many hints in Mifflin's poetry that something was wrong and that he was missing something. He was attending a party when he pulled his cousin aside and informed him he was going to ask Barbara Peart, a "chestnut-haired" woman from Columbia, to marry him. His cousin looked at him and told him he already asked her, and she had accepted. His loneliness and depression werevisible in his writings. In a collection of poems entitled Ventures in Verse (1876)in the poem "Under the Ban" Mifflin writes:

No cares are mine, on others come

The burdens of my world, While I

Am free to roam-

A mateless bird-

Where'er I will, again to cross

The ocean's foam, or rest, at home.

"You life in like some still stream's flow;

Yours is the goal without the strife,

Thrice happy so!"

Men say. "Atlas!"

I sigh, "Content alone is wealth;

Do ye not know that woe is woe?"

Sad as sad Solomon thou art,

O yearning soul of mine, I said;

One little part

Of leaven, leavens

The whole. Behold! Not a gold barb

Wounds less the heart than a flint dart.

Mifflin's health was strong. He lived for five years past his first stroke. He became epileptic and then after two more strokes, he died on July 16, 1921 in his home, "Norwood," in Columbia.