The fentanyl, which has a value of about $3.5 million, is the largest single shipment of the deadly drug seized by the agency so far.
CBP announced details of the seizure, which took place at the Port of Nogales last Saturday, at a press conference Thursday.
In the same trailer, CBP officers also found another 395 pounds of methamphetamine, valued at about $1.1 million.
The 26-year-old truck driver from Mexico was arrested and turned over to Homeland Security Investigations (HSI), who charged him with two counts of possession with intent to distribute. He remains in federal custody.