As attorney general Clifford gained fame by leading the prosecution in one of the most sensational trials of the 19th century, the Parkman–Webster murder case.

The case, where both victim and assailant were from the upper crust of Boston society, featured the first use of forensic dentistry to secure a conviction.

"[6] The first major case that Clifford prosecuted was for the murder of Boston Brahmin George Parkman, and it was one of the most sensational of the 19th century.

[8] The gruesome method of the body's disposal (which was not complete), the fact that it was a capital crime, and the high status of both victim and accused ensured a great deal of public interest in the case, and the courtroom was packed.

[9][10] Assisted by George Bemis, who had been retained by the Parkman family,[11] he resorted instead to dental forensics and strong circumstantial evidence to build the case against Webster.

[12] There was much controversy afterward concerning the jury instructions given by Chief Justice Lemuel Shaw, but Webster was eventually hanged after confessing the crime.

[9][13] In 1852 the state Whig Party parlayed his popularity in the Parkman case into a nomination for the governorship, which Clifford reluctantly accepted.

[5] The race was a difficult one, dominated by the presidential contest and candidate stands on the state's temperance "Maine law".

[18] Phillips and Clifford traveled to Washington, D.C., in January 1861 to make their appearance before the United States Supreme Court.

[19] At the time, tensions between North and South were exceptionally high, and United States Attorney General Edwin Stanton expressed to them concern that Washington might be attacked by rebel forces.

[20] Clifford was, like other conservative Whigs, politically opposed to the abolitionist movement; he was described by former slave Frederick Douglass as "pro-slavery" and "about the most aristocratic gentleman in Bristol County".

[24] In 1865 Clifford was chosen to act as one of the special counsels prosecuting former Confederate President Jefferson Davis.

Davis was to be prosecuted for treason, but for a variety of reasons the charges were eventually dropped after four years of political and legal wrangling.

[30] In 1875 Clifford was appointed to a diplomatic commission established pursuant to the 1871 Treaty of Washington with the United Kingdom to resolve fishery issues.

However, owing to a delay occasioned by the difficulty in selecting a neutral third commissioner, Clifford never assumed his duties.

[33] Clifford had a friendly and collegial relationship with Chief Justice Lemuel Shaw, who was the father-in-law of writer Herman Melville.