Lymphocytic colitis is a microscopic colitis characterized endoscopically by nearly normal-appearing colonic mucosa and histology demonstrating intraepithelial lymphocytosis. Microscopic colitis that is refractory to conventional therapies, including budesonide, is rare but challenging and with scarce evidence. Upadacitinib is a novel Janus kinase 1 selective inhibitor approved by the US Food and Drug Administration for atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and moderately to severely active ulcerative colitis. We present the first case of lymphocytic colitis refractory to conventional and immunosuppressive therapies, which responded promptly to upadacitinib.