The corporation unanimously elected the Reverend Worthington Smith as seventh president on September 7, 1848. Smith was born in Hadley, Massachusetts, on October 11, 1795. Following graduation from Williams College in 1816, he attended Andover Theological Seminary where he was a student with John Wheeler, Joseph Torrey, and James Marsh. After he graduated from Andover in 1819, he preached for three years before being ordained at the St. Albans Congregational Church on June 4, 1823. He married Mary Little of St. Albans, and they had a family of twelve children. From 1825 he served as a trustee of both UVM and Middlebury. In 1845 the university conferred upon him an honorary degree of doctor of divinity.

President Smith was handicapped by the continuing problem of the university's shortage of funds. Initially he refused the presidency on the grounds that the $1,000 salary was insufficient to provide for a family so large and expensive as mine. After he accepted, his family remained in St. Albans, and it was his custom to return home each weekend, although he sometimes preached on Sunday in neighboring towns.

President Smith was unsuccessful when he attempted to revive the merger negotiations with Middlebury. His most important achievement was the reopening of the medical college in 1854. Celebrations held at UVM in that same year to mark the fiftieth anniversary of the first graduating class reveal that 113 students were enrolled in the undergraduate college, with another 27 in the medical college. The catalogue estimated that student expenses were likely to vary from $87 to $135 a year. Tuition had risen from the original $12 to $30, but room rents were only $4 per annum and board was $2 a week. The entire faculty salary budget for President Smith, five additional professors, and one tutor was six thousand dollars. Burlington, which had experienced three decades of expansion since the opening of the Champlain-Hudson Canal in 1823, had grown to more than 7,500 people as the harbor became a distribution point for lumber and Canadian goods. Church Street was paved in stone in 1851, and gaslights arrived in 1854. Professor George W. Benedict, who had resigned from the faculty, purchased the Burlington Free Press where he served as editor for the next fifteen years.

Shortly after the semicentennial celebration, President Smith's health began to fail, and he submitted his resignation to the corporation on June 27, 1854. His health deteriorated rapidly after his retirement, and he died in St. Albans on February 13, 1856, at the age of sixty.