In the field of aesthetic medicine there is an increasing demand for safe and effective hyaluronic acid (HA) fillers to counteract the aging process. We designed a study to evaluate the safety and histological biocompatibility of Aliaxin® Global Performance, a cross-linked HA filler and Viscoderm® Skinkò E, a product composed of non-cross-linked HA and a complex including vitamins, antioxidants, amino acids and minerals injected into the skin of guinea pigs. Then, we translated our findings into the clinical setting, administering a combination of these compounds to patients seeking a facial rejuvenation procedure targeting moderate-to-severe wrinkles affecting the nasolabial folds. The animal study showed that the two compounds did not induce any significant inflammatory reactions and increased collagen and elastic fibers in the skin. In the clinical setting, injection of Aliaxin® Global Performance, followed by Viscoderm® Skinkò E, resulted in a higher improvement in nasolabial fold hydration, trans-epidermal water loss and wrinkle aesthetic appearance, if compared with a protocol based on Aliaxin® Global Performance alone. In summary, we show evidence on the safety and mechanism underlying two new HA-based compounds of different cross-linkage and composition, proposing that they can be safely used in combination in patients seeking facial rejuvenation procedures with long-lasting efficacy.