Background The aim of this systematic review was to compare clinical, radiographic and patient‐reported outcomes (PROMs) in intra‐bony defects treated with regenerative surgery or access flap. Materials and Methods A systematic review protocol was written following the PRISMA checklist. Electronic and hand searches were performed to identify randomized clinical trials (RCTs) on regenerative treatment of deep intra‐bony defects (≥3 mm) with a follow‐up of at least 12 months. Primary outcome variables were probing pocket depth (PPD) reduction, clinical attachment level (CAL) gain and tooth loss. Secondary outcome variables were Rec, radiographic bone gain, pocket “closure,” PROMs and adverse events. Meta‐analysis was carried out when possible. To evaluate treatment effect, odds ratios were combined for dichotomous data and mean differences for continuous data using a random‐effect model. Results A total of 79 RCTs (88 articles) published from 1990 to 2019 and accounting for 3,042 patients and 3,612 intra‐bony defects were included in this systematic review. Only 10 of included studies were rated at low risk of bias. A total of 13 meta‐analyses were performed. All regenerative procedures provided adjunctive benefit in terms of CAL gain (1.34 mm; 0.95–1.73) compared with open flap debridement alone. Both enamel matrix derivative (EMD) and guided tissue regeneration (GTR) were superior to OFD alone in improving CAL (1.27 mm; 0.79–1.74 mm and 1.43 mm; 0.76–2.22, respectively), although with moderate–high heterogeneity. Among biomaterials, the addition of deproteinized bovine bone mineral (DBBM) improved the clinical outcomes of both GTR with resorbable barriers and EMD. Papillary preservation flaps enhanced the clinical outcomes. The strength of evidence was low to moderate. Conclusion EMD or GTR in combination with papillary preservation flaps should be considered the treatment of choice for residual pockets with deep (≥3 mm) intra‐bony defects.