Objectives: This study aimed to describe the outcomes of a staged procedure combining Descemet membrane endothelial keratoplasty (DMEK) and sutureless scleral fixation (SSF) of a one-piece intraocular lens (IOL) in a case series. Co-performing endothelial keratoplasty (EK) and SSF is associated with intraoperative and postoperative complications such as graft deployment difficulties, air migration, graft detachment, and IOL opacification or tilt, all of which are evaluated in this study. Methods: This is a retrospective observational case series. Clinical data were collected from eight eyes of eight patients who underwent DMEK for endothelial failure and had previously received an SSF with one-piece IOL following complete vitrectomy. During DMEK surgery, an air leak test was conducted to check for air migration into the posterior chamber. If instability was detected, pupilloplasty was performed. Intraoperative and postoperative data, including DMEK graft unfolding time, were collected. Corrected Distance Visual Acuity (CDVA), refraction, endothelial cell density (ECD), central corneal thickness (CCT), intraocular pressure (IOP), and complications were recorded over a 12-month follow-up period. Results: We performed pupilloplasty in four patients (50%). The median CDVA improved from preoperative 0.85 logMAR (range: 0.60 to 1.00) at baseline to 0.18 logMAR (range: 0.10 to 0.70, p = 0.012) at 12 months. The median refraction value changed significantly from −1.00 to −0.50 at 12 months. The median percentage reduction in ECD after 12 months was 33.4% (range 30 to 40). The median baseline CCT was 689 μm (range: 651 to 701) at baseline visit and 541.5 μm (range: 525 to 591, p = 0.008) at 12 months. The median IOP was reduced significantly during follow-up. The median graft unfolding time was 6 min (5 to 9). One patient required rebubbling for partial detachment on postoperative day one. No complications occurred within 12 months. Conclusions: The effective compartmentalization of the anterior and posterior chambers in vitrectomized eyes with an SSF one-piece IOL and pupilloplasty can facilitate critical steps of DMEK surgery in complex eyes. Additionally, the air leak test could prove useful in identifying the need for iris-lens diaphragm reconstruction.