Background and Objectives: Image-guided quantitative and semi-quantitative assessment of skin can potentially evaluate treatment efficacy. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are ideal for this purpose. This study assessed clinically relevant statistical changes in RCM and OCT features in photoaged skin after light and energy-based therapy. Methods: Novel statistical analyses were performed using OCT and RCM data collected during a previously published trial: a 12-week study of female decollete skin randomized to four areas treated with thulium laser (L), photodynamic therapy (PDT), combined L-PDT, and control. Eight semi-quantitative RCM scores of photodamage and OCT measurements of skin roughness, blood flow, and epidermal thickness (ET) were evaluated and compared to dermoscopy and clinical skin scores. In statistical analysis, estimated treatment difference (ETD) was calculated. Results: Twelve women with moderate to severe photodamage were included. RCM and OCT data demonstrated a trend towards rejuvenation of epidermis with increased ET, changes in skin surface, and improved honeycomb pattern in RCM. In angiographic OCT, non-significant changes towards more regular capillary meshes were shown, which matched a decline in appearance of gross telangiectasias in dermoscopy. Improved skin tone after laser and L-PDT was identified in RCM, showing less edged papillae in 36% and 45%, and lentigo number declined in 55% of patients after treatments in dermoscopy. Based on clinical scores, L-PDT provided the greatest clinical improvement, which corresponded to superior ETD outcomes in ET and edged papillae shown in OCT and RCM, respectively. Conclusion: Objective OCT and RCM assessment of skin rejuvenation was demonstrated in this study. Importantly, image-based improvements corresponded to favorable clinical skin scores and fewer photoaging characteristics in dermoscopy. Importantly, most changes did not reach statistical significance, prompting further studies and emphasizing the modest value of non-randomized, non-blinded anti-aging trials.