Objectives Despite the available therapies for treatment-resistant depression (TRD), there are a limited number that are evidence-based and effective in this hard-to-treat population. Esketamine nasal spray, an intranasal N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, is a novel, fast-acting option in this patient population. This manuscript provides expert guidance on the practicalities of using esketamine nasal spray. Methods A group of six European experts in major depressive disorder (MDD) and TRD, with clinical experience of treating patients with esketamine nasal spray, first generated practical recommendations, before editing and voting on these to develop consensus statements during an online meeting. Results The final consensus statements encompass not only pre-treatment considerations for patients with TRD, but also specific guidelines for clinicians to consider during and post-administration of esketamine nasal spray. Conclusions Esketamine nasal spray is a novel, fast-acting agent that provides an additional treatment option for patients with TRD who have previously failed several therapies. The guidance here is based on the authors' experience and the available literature; however, further real-world use of esketamine nasal spray will add to existing knowledge. The recommendations offer practical guidance to clinicians who are unfamiliar with esketamine nasal spray.