Background Osteoarthritis (OA) is a degenerative disease which presents with joint pain and stiffness and reduced mobility. Knee OA is the commonest cause of disability in adults. Dextrose prolotherapy is a new option used to treat mild-to-moderate knee OA. Neural prolotherapy (NPT) is multiple small injections under the skin targeting painful areas with natural substances. The aim of work was to evaluate and compare neural prolotherapy versus intra-articular dextrose prolotherapy effect on relieving pain and improving disability of knee OA. Results VAS and WOMAC scores improved significantly immediately and at 3 and at 6 months, respectively, in group I compared with group II (P < 0.001). The decrease in VAS scores and all the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in group I along the follow-up period in comparison with the baseline scores was statistically significant (P < 0.001). In group II, only WOMAC pain and stiffness scores improved significantly. ROM showed insignificant increase in both groups at 3 and 6 months assessment. On follow-up, range of motion increased in both groups and reached significance in group I (P = .002). Conclusion Dextrose prolotherapy both intra-articular and periarticular (neural) is a very effective and cheap therapy for knee OA with good patient selection. Neural prolotherapy significantly relieves pain and improves function in patients with knee osteoarthritis when compared with intra-articular prolotherapy thus avoiding hazards of intra-articular knee injections.