Background/Objectives: Acanthamoeba keratitis (AK) is a rare but sight-threatening corneal infection. This study reviews the clinical profile, diagnostic pathways, treatment strategies, and outcomes of AK cases managed over a 34-year period. Methods: We conducted a retrospective analysis of 52 microbiologically AK cases from 1983 to 2017. Results: The mean age at presentation was 27.7 ± 9.4 years, with a female predominance (63.5%). The majority (82.7%) were contact lens users, almost exclusively soft lens wearers, with documented risk behaviors such as poor hygiene and sleeping with lenses. 44.2% were initially misdiagnosed as nonspecific microbial keratitis. Common clinical findings included epithelial defects (30.8%), ring infiltrates (44.2%), superficial infiltrates (53.8%), hypopyon (30.8%), and corneal thinning (13.5%). Diagnosis was confirmed by culture/stain in 61.5% of cases, while others required confocal microscopy or corneal biopsy. Co-infections with bacteria were noted in ~20%. Prior to referral, 82.7% of patients had received empirical topical therapy. At KKESH, all received dual anti-Acanthamoeba therapy, and 69.2% underwent surgical intervention, including tectonic PKP (46.2%) and optical PKP (19.2%). Visual acuity improved from a mean logMAR of 1.51 at presentation to 0.87 at last follow-up. Anti-Acanthamoeba therapy was discontinued in 95.9% of patients by the end of follow-up, with steroid use tapering from 61.5% at 3 months to 16.3% at final visit. Conclusions: Acanthamoeba keratitis in Saudi Arabia predominantly affects young female contact lens users and often presents with diagnostic delays and misclassification as herpetic or bacterial keratitis. Despite aggressive medical and surgical therapy, visual outcomes remain suboptimal in many cases.