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Prospective trials of anti-mycobacterial antibiotic therapy (AMAT) have proven efficacious in Crohn&#8217;s disease (CD) but use as first-line treatment in CD has not been evaluated. This paper reports the outcomes of patients with CD treated with first-line AMAT. This paper consists of a case series of treatment-na&#239;ve CD patients who received AMAT as first-line treatment between 2007 and 2014 at a single center. AMAT treatment consisted of rifabutin, clofazimine and clarithromycin, plus either ciprofloxacin, metronidazole or ethambutol. Symptoms, inflammatory blood markers, colonoscopy and histology results, in addition to, the Crohn&#8217;s Disease Activity Index (CDAI) were tabulated from patients&#8217; clinical records, and descriptive statistics were conducted. A Wilcoxon signed-rank test assessed the difference in CDAI scores before and while on AMAT. The statistical significance was set at 5%. Clinical remission (CDAI &lt; 150) with rapid improvement in clinical symptoms and inflammatory markers was seen in all eight patients receiving AMAT as sole therapy by 6 weeks. In all eight patients, the median CDAI score decreased significantly, from 289 prior to treatment to 62 at the 12-month follow-up (<i>p</i> &lt; 0.001). Follow-up colonoscopies showed healing of CD ulcers, no visible mucosal inflammation, restoration of normal vascular patterns and complete mucosal healing on histology samples. AMAT as first-line therapy demonstrated a rapid improvement of Crohn&#8217;s disease (not previously seen when used as second-line therapy).