With the merger in 1865 of Transylvania College, Kentucky University (in Harrodsburg), and the newly state-chartered Agricultural and Mechanical College of Kentucky, Patterson was appointed professor of Latin and Civil History in this enlarged "Kentucky University". At the same time he secured the chair of History and Metaphysics, which he occupied, under changing institutional auspices, until 1910. In 1869 Patterson was elected third Presiding Officer of the University's now constituent Agricultural and Mechanical College. After rancorous denominational and theological bickering and debilitating financial hardship experienced by the hybrid institution, the State Legislature in 1878 formally separated the A&M College from K.U., and Patterson assumed the position of "President" of the independent school.
One of the A&M president's first administrative efforts, following the erection of the college's first buildings on its new Lexington Fairgrounds site, ultimately at his own expense, was an attempt to repair the fiscal damage incurred by the school during its preceding thirteen years of existence in linkage with Kentucky University. To this end he indefatigably led the fight to convince the Kentucky General Assembly to enact legislation establishing a one-half-cent state property tax to raise desperately needed monies to support the struggling College. The climax of his crusade-an impassioned speech on the floor of the Senate-- succeeded in sweeping away the formidable, organized opposition to the tax, and the measure was approved in 1882. The revenues from this new tax, however, proved insufficient to provide for the college's stability and continued growth. With the financial situation of the institution in question, Patterson considered other means of fundraising. When all other options had been exhausted he secured a personal loan to procure the needed money.
Patterson proved a capable chief executive, administering the daily operations and affairs of the A&M College wisely and economically, although he was criticized by his detractors as unduly tyrannical and miserly, the latter particularly as it related to the salaries of employees and to physical expansion. Many in the community and state likewise felt that the president was wrongly removing the college from its moorings in agricultural and engineering instruction, as mandated by the Morrill Land-Grant Act, and setting it on a course of becoming an essentially liberal arts institution.
Increasing curricular diversification led to moves to upgrade A&M's official academic classification, and Patterson and his Board of Trustees in 1908 successfully lobbied the General Assembly in support of changing the school's name to: "State University, Lexington, Kentucky". He continued as President for two more years, assisting in the transition of the institution to University status. In 1910 he retired from the presidency. The Board of Trustees unanimously approved his stipulated conditions which included: attendance at Board and faculty meetings; serving as advisor to the incoming President and as representative of the University on the state and national level; and continued residence in the campus house built for the President in 1882, which he occupied until his death in 1922. The life and legacy of Kentucky's "Pater Universitatis" are today honored in University buildings and a roadway which bear his name, and in the great seated statue of the founder, erected in 1934, which sits adjacent to the institution's Administration Building and astride the campus he built and nurtured.