Background: Acute rejection (AR) in kidney transplant (KT) recipients remains a significant challenge for short- and long-term graft survival even in the most recent years characterized by extended criteria donors and older and more comorbid recipients. Methods: We analyzed risk factors and outcomes of AR in 339 KT recipients treated at St. Orsola-Malpighi Hospital, Bologna (Italy), between 1 January 2019 and 31 December 2021. Demographic, immunological, and transplant data (type, cold ischemia time, complications) were recorded with a follow-up period of up to 24 months. Key outcomes included estimated glomerular filtration rate (eGFR), 24 h proteinuria, delayed graft function (DGF), biopsy-proven AR, and graft loss. Results: During the first year after transplant, 57 AR episodes occurred: 19 antibody-mediated rejections (AMR), 18 borderline T cell-mediated rejections (TCMR), 18 TCMR, 2 mixed AMR/TCMR, and 11 graft losses. AR was linked to older donor age (59.9 ± 12.8 vs. 55.5 ± 15.1, p = 0.040), longer cold ischemia time (690 vs. 570 min, p = 0.044), higher DGF rates (61.40% vs. 39.57%, p = 0.002), and lower eGFR (39 vs. 52 mL/min, p = 0.003). AR was consistently prevalent in patients who underwent an AB0-incompatible (AB0-i) transplant (8.8% vs. 2.5%, p = 0.020). HLA matching was strongly associated with a reduced risk of AMR (HLA-DR: OR 0.35, HLA-A: OR 0.33, HLA-C: OR 0.35), while DGF was linked to a higher risk (OR 4.04). TCMR risk was associated with donor age (OR 1.05). The development of post-transplant donor-specific antibodies (DSAs) at 24 months showed no significant association with AR (AMR: p = 0.769; TCMR: p = 0.938). The decline in eGFR over time (24 months) did not differ between patients with and without AR (difference, −0.69 mL/min/year; Standard Error, 0.92; p = 0.452). Similarly, 24 h proteinuria change over time did not differ between patients with and without AR (difference, −0.12 g/24 h; Standard Error, 0.28; p = 0.657). Conclusions: Understanding the risk factors of AR is crucial to identifying KTs at more risk of rejection and to guiding targeted therapeutic decisions. In the most recent era of extended criteria donors and more vulnerable recipients, early diagnosis and prompt and tailored treatment of AR play a critical role in stabilizing renal function over time.