He handled all types of cases, ranging from property law to criminal law to admiralty law. He became well known for some of his criminal defense work. In 1769 he successfully defended several American sailors who were charging with murdering a British naval officer who had come upon their ship. Pleading that his clients acted out of self-defense, Adams obtained a not guilty verdict from the jury.

In a more famous case, in 1770 Adams defended several British soldiers who fired upon a growing mob of people on a Boston street. The tragic event became known as the Boston Massacre. Adams successfully defended the British captain, Thomas Prescott, who was in charge of the troops who fired upon the crowd. Adams earned a not guilty verdict for Prescott. Adams also defended eight other British soldiers tried for their alleged role in the Boston Massacre. He earned six not guilty verdicts and reduced charges of manslaughter for the other two.