Background: Osteoarthritis (OA) of the knee is the most common joint disease, characterized by the degeneration of joint cartilage. Intra-articular hyaluronic acid (IAHA) injections are a well-established non-surgical treatment. Methods: This retrospective study analyzed knee OA patients receiving IAHA combined with niacinamide injections, assessing pain reduction in relation to patient data, the number of injections, and radiological findings. Results: IAHA injections led to significant pain reduction on the numeric rating scale (NRS) (0–10), with a mean decrease of 3.34 ± 1.65. Pain relief was greater with multiple injections. A comparison of subgroups by injection frequency (1, 2, or >2) showed significant pain reduction between 1 and 2 injections (p = 0.027) and between 1 and >2 injections (p = 0.032). The OA grade measured using the Kellgren–Lawrence (p = 0.95) and Vallotton MRI classifications (p = 0.50) did not correlate with pain reduction. However, patients with meniscal damage (p = 0.02) showed a greater benefit. A strong positive correlation was found between baseline pain intensity and pain reduction (p < 0.001; r = 0.61). Conclusions: IAHA with niacinamide significantly reduces knee OA pain, with more injections enhancing pain relief. Greater benefits were observed in patients with higher baseline pain and meniscal damage. The favorable safety profile and potential for repeated treatments make IAHA a valuable option in knee OA management.