House was born and grew up in rural Lily, Laurel County, Kentucky, but he also spent much of his childhood in nearby Leslie County, Kentucky, which he has cited as the basis for the fictional Crow County, which serves as the setting for his first three novels. He has degrees from Sue Bennett College (Associate's), Eastern Kentucky University (BA in English with emphasis on American literature), and from Spalding University (Master of Fine Arts in Creative Writing). In 2000, House was chosen, along with since-published authors Pamela Duncan, Jeanne Braselton, and Jack Riggs, as one of the ten emerging talents in the south by the Millennial Gathering of Writers at Vanderbilt University.

House is also a music Journalist and a contributing Editor to No Depression magazine, for which he has written features on Lucinda Williams, Delbert McClinton, and many others. House is also an in-demand press kit Writer for Nashville's music Business, having written biographies for such artists as Kris Kristofferson, Buddy Miller, Del McCoury, and Lee Ann Womack. In 2001 and 2002, he was a regular contributor to NPR's All Things Considered.

House served as a Writer in residence at Eastern Kentucky University 2004-2005 and at Lincoln Memorial University 2005-2010. At LMU he also created and directed the Mountain Heritage Literary Festival and the Appalachian Reading Series. In 2010 House became the NEH Chair in Appalachian Studies at Berea College in Berea, Kentucky, where he teaches Appalachian Literature and a writing workshop. He served for one year, 2011-2012, as interim Director of the Loyal Jones Appalachian Center. He has served on the fiction faculty at Spalding University's MFA in Creative Writing since 2005.

Between 2005 and 2010 House was very visible in the fight against mountaintop removal mining, an environmentally devastating form of coal mining that blasts the entire top off a mountain and fills the valley below with the debris. House says he got involved in the issue after being invited on a tour of devastated mountains by Environmentalist, author, and public intellectual Wendell Berry. House wrote the original draft of the 2005 Kentucky authors' statement against the practice; since the draft more than three dozen authors have signed it. House has published many articles about mountaintop removal, including an editorial in The New York Times. House serves on the board of Appalachian Voices, the major clearing house for grassroots organizations fighting mountaintop removal, was a speaker in 2011 at Appalachia Rising, a major protest in Washington D.C. that resulted in more than 115 arrests, and in 2013 was the keynote speaker at I Love Mountains Day.

House's fourth novel, Eli the Good, was published in September 2009 to great acclaim. The book emerged as a number one bestseller on the Southern lists and received the first annual Storylines Prize from the New York Public Library system, an award given to a book for use in the ESL and literacy programs of New York City.

In 2010 House was selected as the focus of the Silas House Literary Festival at Emory and Henry College in Emory, Virginia. The same year he was chosen as Appalachian Writer of the Year by Shepherd University in Shepherdstown, West Virginia.

House's first book for middle-graders, Same Sun Here, was published in February 2012 and co-written with Neela Vaswani. The book was the winner of the Parents Choice Award and was the #1 Most Recommended Book by Independent Booksellers in the entire nation during the Spring of 2012. House and Vaswani recorded the highly successful audiobook version of the novel, which won an Earphones Award, and the Audie Award for Best Narration, the highest honor given to audiobooks.

In recent years House has become increasingly outspoken on bullying and fairness issues. He wrote an editorial for The New York Times about the fight for gay equality in small towns that led to him being invited to speak at the Library of Congress in August 2015. In 2017, he participated in the Women's March in Lexington, Kentucky, as one of the main speakers.

House was born and raised in Southeastern Kentucky. He presently lives in Berea, Kentucky. House's next novel is Southernmost, which will be published in Spring 2018 by Algonquin Books.