On December 1, 1962, USS Greene changed home port to Boston, Massachusetts and the ship was placed in reserve commission at Boston Naval Shipyard to undergo Mark I Fleet Rehabilitation and Modernization (FRAM I) . This was the second major conversion of the ship and the FRAM I program included an overhaul and extensive modernization of the entire ship. The ship's complement was reduced to five officers and approximately 80 enlisted men.

One of the ship's five-inch guns was removed as were all three-inch guns and the depth charges. ASW torpedo tubes were added, as well as, the ASROC launcher, the DASH hanger and deck, and the SPS-40 radar. In the last step of the evolution of the USS Greene's mission, the emphasis was on anti-submarine warfare, electronics, and electronic counter measures.

After post FRAM I check out USS Greene joined Task Group Alpha , Destroyer Squadron 32, and conducted Hunter-Killer (HUK) exercises in both the Atlantic and Mediterranean. In 1965 the ship carried out duties as a recovery ship for the unmanned Gemini Space Shot in the Caribbean and took part in patrol duties off the Dominican Republic. In early 1966 USS Greene was named the winner of the Atlantic Fleet Anti-Submarine Warfare Trophy and received an "A" for ASW excellence.

On June 1, 1966, USS Greene departed Norfolk, Virginia in the company of USS Beale (DD-471) for duty in the Seventh Fleet . On June 6, 1966, USS Greene transited the Panama Canal and entered the Pacific Ocean for the first time in her career . USS Greene had now operated with all four of the Navy's numbered Fleets. She truly lived up to her new motto "Anywhere-Anytime". After transiting the Panama Canal USS Greene hit a submerged log. She entered Pearl Harbor, Hawaii on June 21, 1966, to have the starboard screw replaced and a flooded rudder repaired. With repairs made she departed Hawaii, crossed the International Date Line on June 30, 1966, and headed for Viet Nam service. After departing Hong Kong on July 27, 1966, USS Greene was underway for "Yankee Station" in the Tonkin Gulf. During most of this period she was an escort and rescue ship for the USS Constellation (CVA-64) and USS Coral Sea (CVA-43) as the ships conducted air strikes against North Vietnam . USS Greene also provided Naval Gunfire Support to friendly forces in the Republic of Vietnam's I Corps Area. This was the only time that USS Greene's five inch guns were fired in anger.

On October 19, 1966, just two days out of Sasebo, Japan and just joining the USS Roosevelt (CVA-42) , the ship's port shaft parted in the stern tube and slid aft to rest on the port rudder. USS Greene limped into Tso Ying, Taiwan. The ship's propeller was locked in place, and then USS Greene transited to Subic Bay, Philippine Islands for repairs. On November 10, 1966, USS Greene departed Subic Bay, Philippine Islands, crossed the Equator and then began the 13,396 mile transit back to Norfolk, Virginia. After brief visits in Pulau, Singapore; Cochin, Indian and Aden, Aden USS Greene passed through the Malacca Straits and Suez Canal to circumnavigate the world. USS Greene arrived in Norfolk, Virginia on December 17, 1966.

USS Greene departed Norfolk, Virginia on November 2, 1967, for the first leg of her Red Sea cruise and as a unit of the Middle East Force. She rounded the Cape of Good Hope and proceeded along the east cost of Africa. The ship spent Christmas in Mombassa, Kenya. Ports of call included: Port Louis, Mauritius; Djibouti, French Somaliland; Jidda, Saudi Arabia and Massawa, Ethiopia. On February 3, 1968, after firing a twenty-one gun salute to welcome his royal highness, Prince Ghalamreza Pahlavi, brother of the Shah-of-Iran, USS Greene ran aground as she entered the harbor of Bandar Abbas, Iran. The ship was freed the next day and proceeded to Karachi Shipyard and Dry-dock Company in Karachi, Pakistan to repair the starboard propeller and crushed (SQS 23) sonar dome.

USS Greene returned home from the Middle East on May 14, 1968. Two weeks later she was part of the massive search for the missing submarine USS Scorpion (SSN-589). USS Greene participated in NATO Convoy Exercise "Silver Tower", the first exercise of its type since WW II, and in October 1968 she assisted in the recovery of the manned space craft Apollo VII.

After being placed in CADRE status in November 1968 (35% of normal manning level), USS Greene was not placed in fully operational status until the fourth quarter of 1969. On December 1, 1969, USS Greene was removed from CADRE status and commenced her Refresher Training with a new crew. However, recurring propeller and shaft problems continued to curtail her readiness capability.