Kammala jumla mai zuwa: A lokacin Yakin Mexico-Amurka (1846-1848), Twiggs ya jagoranci brigade a cikin Sojojin Kasuwanci a yakin da aka yi a
Palo Alto da kuma Resaca de la Palma. An gabatar da shi ga brigadier janar a 1846 kuma ya umurci wani rukuni a yakin Monterrey. Ya shiga Winfield Scott yawon shakatawa, umurnin ta 2nd Division na Regulars. Ya jagoranci rukunin a duk yakin da aka yi daga Veracruz zuwa Mexico City. An ji masa rauni a lokacin da aka kai hari a Chapultepec. Bayan faduwar Birnin Mexico, an nada shi gwamnan soja na Veracruz. An ba da Brigadier Janar Twiggs takobin bikin ta Majalisa a ranar 2 ga Maris, 1849. Ya kasance memba na asali na Aztec Club na 1847, ƙungiyar soja na jami'ai waɗanda suka yi aiki a cikin Yaƙin Mexico.