A severe and progressive interstitial lung disease (ILD) known as idiopathic pulmonary fibrosis (IPF) has an unknown etiology with poorly defined mechanisms of development. Among the currently prescribed pharmacological interventions for IPF, nintedanib demonstrates the ability to decelerate the deterioration of lung function and yield positive clinical outcomes. Multiple randomized placebo-controlled trials have confirmed the efficacy and acceptable safety profile of nintedanib. Real-world evidence studies also support the use of nintedanib in IPF, being an efficient and well-tolerated treatment option. It has the potential to stabilize the disease progression in patients with ILD. Patients with IPF frequently have comorbidities like diabetes and hypertension, which can exacerbate the course of disease, reduce quality of life, and decrease treatment adherence. For well-informed decision-making, it is important for healthcare professionals to recognize the position of nintedanib therapy in IPF with comorbidities. The gastrointestinal adverse effects, notably diarrhea, dominate the nintedanib safety profile. These can be effectively controlled by closely monitoring side effects, administering anti-diarrheal and anti-emetic drugs, reducing the nintedanib dose, and discontinuing it in case of severe symptoms with an option to reintroduce the treatment after side effects subside. Symptomatic interventions and monitoring of liver enzymes may reduce the occurrence of permanent treatment discontinuations.