Tightly focused femtosecond laser pulses are widely used in the biomedical field due to their nonlinear multiphoton precision and minimal thermal side effects. Below the threshold of optical breakdown, light energy contributes to photochemical reactions that introduce more chemical bonding in the form of collagen crosslinking (CxL) in extracellular matrices of transparent tissues such as corneal stroma. Previously, based on the principles of ultrafast laser-tissue interaction, a novel collagen CxL method relying on low-density plasma (LDP) generating reactive oxygen species (ROS) was proposed and applied to cornea tissue for vision correction by the Vukelic Group and extended to articular cartilage tissue for early osteoarthritis treatment in collaboration with Musculoskeletal Biomechanics Research Laboratory. Despite the efficiency and safety of the procedure, LDP was elusive and challenging to control due to its potential dependence on a cascade of intertwining factors such as ultrafast laser wavelength, power, pulse duration, repetition rate, and ionization resonance. This thesis has two aims: the first is to investigate the photochemical laser-tissue interaction with femtosecond nanojoule energy pulses, and the second is to develop robust and practical laser parameter envelopes for treating corneal ectatic diseases and osteoarthritis. Chapter 2 proposes a corneal epithelium-stromal level wound healing treatment. Relying on the interaction between reactive oxygen species (ROS) created by low-density plasma (LDP) therapy and inflammatory cytokines, epithelium recovery is accelerated on in vivo rabbit corneas. Chapters 3 to 5 focus on photochemical reaction-based morphological correction and biomechanical enhancement for corneal diseases such as keratoconus and astigmatism. A wavelength-independent, nonenzymatic CxL technique based on oxygen-independent, pentose-mediated glycation and ROS acceleration is developed; collagen CxL efficiency is tested through autofluorescence microscopy and nanoindentation. Subsequently, the combined effects of simultaneous external mechanical loading and nonenzymatic collagen CxL, achieved by both traditional CxL that involves soaking eyes with riboflavin solution, a photosensitizer, and then activating it with ultraviolet A light (UVA-Riboflavin-CxL) and new ROS catalyzed glycation CxL (ROS-Glycation-CxL) techniques, are investigated on ex vivo rabbit corneas. Through X-Ray Diffraction, permanent adjustments to the ultrastructure of collagen fibril packing are observed, ultimately contributing to refractive power changes in corneal topography. Furthermore, with the addition of melanin application that increases absorption and ionization efficiency, a robust method for generating plasma and reactive oxygen species (ROS) is proposed and implemented on ex vivo corneas to address ectatic diseases. Chapter 6 discusses the effect of plasma-guided laser collagen CxL on articular cartilages’ compressive equilibrium modulus and chondrocyte viability. Stemming from the melanin-assisted protocol and ultrafast pulses' high peak power, a plasma spark-mediated laser treatment is hypothesized to biomechanically enhance both bovine and human articular cartilage superficial zone for the treatment of osteoarthritis. Chapter 7 concludes this thesis and proposes future directions.