The division was mobilised on 5 August 1914, the day after Britain declared war on Germany. On 20 August the entire division moved to Chelmsford, Bury St Edmunds and Norwich. The division spent the next few months on home service and coastal defence and started training in preparation to eventually go overseas. In May 1915 the East Anglian Division was numbered as the 54th Division and all the brigades in the division were also numbered—the Norfolk and Suffolk Brigade became 163rd Brigade. As happened in all Territorial Force divisions, the battalions were also numbered and adopted the '1/' prefix, to distinguish them from their 2nd Line units which were being formed. The 2nd Line were initially intended to act as a draft-finding reserve for the 1st Line. They were the 208th Brigade, 69th Division. In November 1914 the 1/4th Battalion, Suffolk Regiment was transferred to the 3rd Division of the British Indian Army and were replaced in the brigade by the 1/8th Battalion, Hampshire Regiment, which was previously unattached to a field formation. In July 1915 the division was ordered to prepare for overseas service. The brigade served with the 54th Division in the Middle Eastern theatre and fought in the Gallipoli Campaign, landing at Suvla Bay on 10 August 1915, as part of IX Corps. During the fighting on 12 August the 1/5th Norfolks "...were on the right of the line", wrote Sir Ian Hamilton, commanding all forces in the region "and found themselves for a moment less strongly opposed than the rest of the brigade. Against the yielding forces of the enemy Colonel Sir Horace Beauchamp, a bold, self-confident officer, eagerly pressed forward, followed by the best part of the battalion. The fighting grew hotter, and the ground became more wooded and broken. At this stage many men were wounded, or grew exhausted with thirst. These found their way back to camp during the night. But the colonel, with sixteen officers and 250 men, still kept pushing on, driving all the enemy before them. Nothing more was ever seen or heard of any of them. They charged into the forest and were lost to sight or sound. Not one of them ever came back." The men, the so-called vanishing Norfolks, were the subject of a BBC TV film, All the King's Men. The division was evacuated from Gallipoli in early December and spent the most of 1916 in Cairo, Egypt, occupying No. 1 Section of the Suez Canal defences. The division fought again in 1917 and invaded Palestine. The brigade fought in the First Battle of Gaza in late March, Second Battle of Gaza in mid-April and Third Battle of Gaza in late October – early November battles of Gaza and the Battle of Jaffa in December. In 1918 the brigade fought at Berukin from April to May and finally at the Battle of Sharon in mid-September. The division concentrated at Beirut between 31 October and 5 November, but the Ottoman Empire surrendered on 31 October with the signing of the Armistice of Mudros.
The brigade was disbanded after the war, along with the rest of the Territorial Force. However, it was reformed, as the 163rd Infantry Brigade, in the Territorial Army and continued to serve with the 54th Division and had the same four battalions as it did before the First World War. However, in 1921, the 4th and 5th battalions of the Suffolks were amalgamated as the 4th/5th Battalion, Suffolk Regiment. The brigade later received the 1st Battalion, Cambridgeshire Regiment from the 162nd Infantry Brigade. The composition of the brigade remained this throughout much of the inter-war period. In 1938, however, the 1st Battalion, Cambridgeshire Regiment was transferred back to 162nd Infantry Brigade, when all British infantry brigades were reduced to three battalions.
In World War II, the brigade continued to be part of the 54th Infantry Division from September 3, 1939, to December 13, 1943, when that division was disbanded. The brigade then became a Lines of Communication unit for the 21st Army Group. It stayed in the United Kingdom for the duration of its service. The original battalions of the brigade were converted into the 53rd Infantry Brigade, joining the 18th Infantry Division, on 18 September 1939 and the 163rd Infantry Brigade was reformed from the redesignation of the 161st Infantry Brigade. Second World War commanders of the brigade included Brig. M.D. Jephson, Brig. R.A.D. Moseley, Brig. O.M. Wales, and Lieut.Col. A.L. Taffs.