In 1900, Lettow - Vorbeck was posted to China as a member of the international alliance forces to quell the Boxer Rebellion. He was next posted to Africa.

Beginning in 1904 he was assigned to German South - West Africa (now Namibia), during the Namaqua and Herero insurrection. However, he did not participate in the subsequent genocide. Having suffered injuries to his left eye and chest, he was evacuated to South Africa for treatment and recovery.

In 1907 he was promoted to major and assigned to the staff of 11th Army Corps. From March 1909 to January 1913 Lettow - Vorbeck was commander of the marines of II. Seebatallion [2nd Sea Battalion] at Wilhelmshaven in Lower Saxony, Germany. As a lieutenant colonel, in October 1913 he was appointed to command the German colonial forces known as the Schutztruppe (protection force) in German Kamerun (today's Cameroon plus a portion of Nigeria). Before he could assume this command, however, his orders were changed and he was posted — effective 13 April 1914 — to German East Africa, the mainland of present Tanzania.

In August 1914, during the early phases of the World War I, Lettow - Vorbeck was the commander of a small garrison of just 2,600 German nationals and 2,472 African soldiers in 14 Askari field companies. Realising the need to seize the initiative, he ignored orders from Berlin and the colony's governor, Heinrich Schnee, who had insisted on neutrality for German East Africa. Lettow - Vorbeck simply ignored the governor and prepared to repel a major amphibious assault on the city of Tanga. The attack began on 2 November 1914, and for the next four days he fought one of his greatest battles. He then assembled his men and their scant supplies to attack the British railways in East Africa. He scored a second victory over the British at Jassin on 18 January 1915. These victories gave him badly needed modern rifles and other supplies, as well as critical boost to the morale of his men. However, Lettow - Vorbeck also lost many experienced men, including the "splendid Captain Tom von Prince," whom he could not easily replace.

Lettow - Vorbeck's plan for the war was quite simple: knowing that East Africa would only be a sideshow, he determined to tie down as many British troops as he could. He intended to keep them away from the Western Front, and in this way contribute to Germany's eventual victory.

Lettow - Vorbeck knew he could count on his highly motivated officers (their casualty rate was certainly proof of that). As a consequence of costly personnel losses, he afterwards avoided direct engagements with British forces, instead directing his men to engage in raids into British East Africa (modern Kenya), Uganda and Rhodesia, targeting forts, railways and communications — all with the goal of forcing the Entente to divert manpower from the main theater of war in Europe. He realized the critical needs of guerrilla warfare in that he used everything available to him in matters of supply.

The Schutztruppe recruited new personnel and expanded to its eventual size of some 14,000 soldiers, most of them Askari, but all well trained and well disciplined. Lettow - Vorbeck’s fluency in the Swahili language earned the instant respect and admiration of his African soldiers; he appointed black officers and "said — and believed — 'we are all Africans here'." "It is probable that no white commander of the era had so keen an appreciation of the African’s worth not only as a fighting man but as a man."

He gained the men and artillery of the German cruiser SMS Königsberg (scuttled in 1915 in the Rufiji River delta) which had a capable crew under commander Max Looff, as well as its numerous guns, which were converted into artillery pieces for the land fighting, which would be the largest standard land artillery pieces used in the East African theater. In March 1916 the British under Gen. J.C. Smuts launched a formidable offensive with 45,000 men. Lettow - Vorbeck patiently used climate and terrain as his allies while his troops fought the British on his terms and to his advantage. The British, however, kept on adding more troops and forcing Lettow to yield territory. Nevertheless, he fought on, including a pivotal battle at Mahiwa in October 1917 where he lost 519 men killed, wounded or missing and the British 2,700 killed, wounded or missing. After the news of the battle reached Germany he was promoted to Generalmajor. The British would recover their losses and continue to hold an overwhelming manpower advantage; for the Schutztruppe it was serious, there were no reserves to again fill the ranks.

Lettow - Vorbeck now began a forced withdrawal to the south, with his troops at half rations and the British in pursuit. On 25 November 1917 his advance column waded across the river Rovuma into Portuguese Mozambique. In essence he cut his own supply lines and the Schutztruppe caravan became a nomadic tribe. On their first day across the river they attacked the newly replenished Portuguese garrison of Ngomano and solved all their supply issues for the foreseeable future. When they captured a river steamer with a load of medical supplies, including quinine, at least some of their medical problems were no more. For almost an entire year they had now lived off the land, but mainly with provisions captured from the British and Portuguese; they had replaced their old rifles with new equipment and acquired machine guns and mortars after capturing Namakura (Nhamacurra in modern Mozambique) in July 1918. At the end they had more ammunition than they could carry.

On 28 September 1918 von Lettow again crossed the Rovuma and returned to German East Africa with the British still in pursuit. He then turned west and raided Northern Rhodesia, thus evading a trap the British had prepared for him in German East Africa. On 13 November 1918, two days after the armistice, he took the town of Kasama which the British had evacuated, and continued heading south - west towards Katanga. When he reached the Chambeshi River on the morning of 14 November, the British magistrate Hector Croad appeared under a white flag and delivered a message from the allied General van Deventer informing him of the armistice. Lettow - Vorbeck agreed to a cease fire at the spot now marked by the Von Lettow - Vorbeck Memorial in present day Zambia. He was instructed by the British to march north to Abercorn (now Mbala) to surrender his undefeated army, which he did there on 23 November. His remaining army then consisted of 30 German officers, 125 German non-commissioned officers and other enlisted ranks, 1,168 Askaris and some 3,500 porters.
The British and Belgian invasions of German East Africa set off a chain of events with devastating ramifications for the natives and their German overlords. The invasions caused interruptions throughout the colony so that the land no longer “basked in a climate of plenty.”

As military commander, Lt. Col. von Lettow - Vorbeck’s first obligation was to his army over the objections of Governor Heinrich Schnee. The governor regarded war as the worst possible calamity that could befall German East Africa; it would “undo everything his social and economic reforms had accomplished.” Lettow - Vorbeck knew he would have to give ground and escape confrontations with Allied forces. He thus established food depots along his intended line of march from Neu Moshi to the Uluguru Mountains, and if the neighboring villages were near starvation, that was a misfortune of war.

Hardly any aid from Germany could penetrate the British blockade to alleviate the enormous supply deficiencies, and only two blockade runners succeeded in reaching the colony. On 14 April 1915 the freighter Kronborg arrived off Tanga at Manza Bay after a two months' journey from Wilhelmshaven, and was promptly attacked by the British cruiser Hyacinth. Fortunately for the Germans, Kronborg had been scuttled by her captain to avoid a coal fire after repeated hits by the British cruiser and the ship settled in shallow water. Nearly its entire cargo could be salvaged. When the steamer Marie von Stettin arrived south of Lindi on 17 March 1916, its precious cargo of 1,500 tons was of only very modest help. A November 1917 attempt to resupply German forces by a Zeppelin airship failed. By late September 1916, all of coastal German East Africa, including Dar es Salaam and the Central Railway, were under British control, with the west occupied by Belgians; then during December 1917 the German colony was officially declared an Allied protectorate.

Lettow - Vorbeck and his caravan of Europeans, askaris, porters, women and children marched on, deliberately bypassing the tribal home lands of the native soldiers in an effort to forestall desertions. They traversed difficult territory, “swamps and jungles . . . what a dismal prospect there is in front of me [to succeed]” stated the Allied commander Gen. J.C. Smuts. But Smuts did not flinch. His new approach and objective was not to fight the Schutztruppe at all, but to go after their food supply. The end eventually came some time later with Smuts in London and Gen. J.L. van Deventer in command in East Africa.

In a 1919 book, Ludwig Deppe, a medical doctor campaigning with Lettow - Vorbeck and former head of the hospital at Tanga, looked back in rue and lamented the tragedy that was imposed by German forces on East Africa in their war with the invading Allies: “Behind us we leave destroyed fields, ransacked magazines and, for the immediate future, starvation. We are no longer the agents of culture, our track is marked by death, plundering and evacuated villages, just like the progress of our own and enemy armies in the Thirty Years' War.”

While there was German callousness and harshness, the new British or Belgian masters in German East Africa were by no means benevolent, either. They assumed no responsibility for African welfare and provided little assistance to the malnourished native population; indeed, when food ran short for the Allied formations “the British askaris fell back on the practice of attacking and looting villages.” When the worldwide Spanish influenza epidemic swept into eastern Africa in 1918 - 19 it struck down thousands with impartiality, native and European alike. The weakened state of many natives made them especially susceptible; this included the caged askaris and porters of the German Schutztruppe, which had been herded together at the Tabora POW camps.

After hostilities ended, the British transferred the German soldiers and POWs to Dar es Salaam for eventual repatriation. Lettow - Vorbeck tried to ensure decent treatment and the briefest time the German askaris would be caged at Tabora.