(1) Background: Retinal degeneration develops upon caspase-12 activation in aged BALB/c mice following systemic neonatal infection. (2) Methods: MCMV or medium was injected intraperitoneally (i.p.) into caspase-12^−/− and caspase-12^+/+ mice (on BALB/c background) at <3 days after birth. At 8 and 12 months post infection (p.i.), eyes were analyzed by SD-OCT before eyes and extraocular tissues were collected and analyzed by plaque assay, H&E staining, TUNEL assay, Western blot and real-time RT-PCR. (3) Results: Virus DNA, but not replicating virus, was present in eyes and extraocular tissues at 8 and 12 months p.i. Several MCMV genes were expressed in eyes of both MCMV-infected caspase-12^−/− and caspase-12^+/+ mice, while mean retinal thickness was significantly higher in MCMV latently infected aged caspase-12^−/− mice compared to age-matched infected caspase-12^+/+ mice. Although similar levels of cleaved caspase-1 were detected in eyes of both infected caspase-12^−/− and control mice, significantly higher levels of activated NF-κB, cleaved caspase-8, MLKL, p-RIP3 and p53 were observed in eyes of infected caspase-12^+/+ mice compared to eyes of infected caspase-12^−/− mice. (4) Conclusions: Our results suggest that caspase-12 contributes to retinal degeneration during MCMV ocular latency via multiple pathways including apoptosis and necroptosis.