This study investigated whether Ganoderma lucidum (Y2)-mediated fermentation of Artemisia capillaris extract (ACE) could synergistically enhance its antioxidant, anti-inflammatory, and tyrosinase-inhibiting activities. Both G. lucidum extract and fermented ACE exhibited 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability, but with poorer efficacy than ACE (even at a low ACE concentration). Viability of RAW264.7 macrophages was significantly reduced in the presence of ACE (150 mg/mL and above). However, this effect was greatly mitigated upon G. lucidum-mediated ACE fermentation. Additionally, relative to the same concentration (25 μg/mL) of G. lucidum mycelial extract, ACE exhibited an improved ability to significantly inhibit RAW264.7 macrophage nitric oxide (NO) production. Finally, relative to the same concentration (200 μg/mL) of a positive control (arbutin), fermented ACE exhibited an approximately 3.66 times higher capacity for tyrosinase inhibition. These results suggest that G. lucidum-fermented ACE possesses enhanced tyrosinase-inhibiting activity and may be of utility as a skin-lightening agent.