The introduction of tumor necrosis factor (TNF) inhibitors has significantly changed the treatment landscape in Crohn's disease (CD). The overall therapeutic achievements with TNF inhibitors such as infliximab, adalimumab, and certolizumab pegol paved the way to push the boundaries of treatment goals beyond symptomatic relief and toward cessation of objective signs of inflammation, including endoscopic remission. Even though these agents are widely used for the treatment of moderate to severe CD, heterogeneity still exists in translating evidence-based guidelines on the use of anti-TNF agents into actual treatment algorithms in CD. This might be due to several reasons including disparities in health expenditure policies; lack of harmonization between countries; and variations in assessment of disease severity, use of disease monitoring tools, or application of treatment targets by physicians. With the advent of biosimilars, patent-free versions of reference biologics are now available to minimize health inequalities in drug availability. In this context, this article aims to provide practical clinical guidance for the use of infliximab and adalimumab biosimilars in patients with moderate to severe CD by outlining different clinical scenarios that patients may encounter during their treatment journey.