This randomized study aims to compare the left atrial (LA) lesion size, function, and tissue damage following pulmonary vein isolation (PVI) by high-power short-duration (HPSD) radiofrequency (RF) and second-generation cryoballoon (CB2) ablation. We enrolled 40 patients with paroxysmal atrial fibrillation who underwent PVI by HPSD RF (n = 21) or CB2 (n = 19). Every patient underwent LA CT angiography and transthoracic echocardiography (TTE) to assess the LA anatomy and function. Biomarker levels (hs-cTnT, hs-CRP, LDH) were compared pre- and post-procedurally. Pre- and post-ablation high-density mapping (HDM) was performed. The isolation area was defined under 0.2 mV bipolar voltage (low voltage area, LVA). We calculated the post-PVI LVA/LA surface ratio using LA CT-HDM merge images. At 3-month follow-up, TTE was performed to assess the changes in LA function. Post-ablation hs-cTnT level was significantly higher in the RF group (RF: 1249 ± 469 ng/L, CB2: 995 ± 280 ng/L, p = 0.024). Post-PVI hs-CRP (RF: 9.53 ± 10.30 mg/L, CB2: 12.36 ± 5.76 mg/L, p = 0.034) and LDH levels (RF: 349.9 ± 65.6 U/L, CB2: 451.6 ± 91.3 U/L, p < 0.001) were significantly higher following CB2 ablation. Post-PVI LVA/LA surface ratios were 8.37 ± 6.42% in the RF group and 13.58 ± 8.92% in the CB2 group (p = 0.022). LA function did not change significantly after the PVI procedure. Our data indicate that second-generation cryoballoon ablation produces a significantly larger LA lesion size compared to “point-by-point” HPSD radiofrequency. Both techniques preserve LA function. The myocardial component of tissue loss appears to be higher using HPSD radiofrequency ablation, with less collateral damage.