Glaucoma progression differs markedly between individuals despite comparable intraocular pressure control, implying additional modifiable contributors to neurodegeneration. We evaluated the joint impact of sleep deficit and inflammatory cytokine trajectories on retinal nerve fiber layer (RNFL) loss. In this 24-month prospective longitudinal observational cohort, 57 participants (19 controls, 19 prostaglandin-treated glaucoma, 19 untreated glaucoma) underwent spectral-domain OCT, validated sleep assessment, and serial IL-6 and TNF-α profiling. Longitudinal models tested independent and interactive effects of sleep deficit and inflammation on RNFL change, and mediation analyses assessed whether inflammation explains the sleep–progression association. RNFL loss rates were −0.20 ± 0.10 μm/year (controls), −1.06 ± 0.89 μm/year (treated), and −1.94 ± 0.78 μm/year (untreated; p < 0.001). Sleep deficit correlated with RNFL loss in glaucoma (r = −0.41, p = 0.010) but not controls, with stronger effects in untreated disease (p = 0.034). Each hour of sleep deficit was associated with 0.09–0.11 μm/year faster RNFL loss (p < 0.05). A combined sleep–inflammation model improved risk stratification (C-statistic = 0.68). Mediation was not supported. Sleep deficit and inflammatory cytokines act as parallel, independent risk factors for glaucoma progression. Integrating sleep and inflammatory profiling may enhance personalized risk assessment beyond pressure-based management.