A sa création, en 1824, elle est décrite comme étant la route de Saint-Pol à Lille et à Tournai. Elle succède alors à la Route impériale 54.
Puis, en 1933, elle devient la route d'Abbeville à Lille, et à Tournai, par Saint-Pol-sur-Ternoise.
En 1973, elle reprend son tracé originel, amputé de la partie d'Englos à la Belgique. Elle devient donc en 1978 la route de Saint-Pol-sur-Ternoise, N. 39, à Lille, A. 25, à Séquedin.
Récemment, la RN41 a été mise en 2x2 voies entre Illies et l'A25. Auparavant, cette portion était assez dangereuse de par ses 3 voies. Au milieu des années 90, les dépassements sur cette portion sont devenus sécurisés. De plus, il existait plusieurs feux en rase campagne respectivement à Fournes-en-Weppes, à Beaucamps-Ligny et à Hallennes-les-Haubourdin.
Les premiers travaux de cette mise à 2x2 voies ont débuté vers l'an 2000.
Un rond-point a été mis en service en août 2007 entre la RN41 et la RN47.
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