Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive motor neuron loss and neuroinflammmation. Current disease-modifying therapies provide only marginal benefit, and microglial NLRP3 inflammasome hyperactivation has emerged as a key pathological amplifier common to all ALS genetic and sporadic subtypes. Colchicine, an anti-inflammatory alkaloid approved for gout and pericarditis, potently inhibits NLRP3 assembly through tubulin disruption and direct blockade of ASC oligomerisation. Hypothesis and Aims: We hypothesise that low-dose colchicine can attenuate microglial NLRP3-driven neuroinflammation in ALS, thereby slowing motor neuron loss and disease progression. We present a mechanistic synthesis of the NLRP3 pathway in ALS, review available clinical and preclinical evidence for colchicine in neuroinflammatory diseases, and propose a precision biomarker-stratified clinical trial design. Methods and Evidence: We performed a systematic review of published literature on NLRP3 inflammasome activation in ALS, colchicine's pharmacology and safety profile, and relevant clinical trial evidence including the Co-ALS randomised controlled trial. Candidate biomarkers for patient stratification and outcome monitoring were identified from the literature. Results: NLRP3 inflammasome activation is documented across ALS subtypes including SOD1, C9orf72, and TDP-43 proteinopathies. Colchicine inhibits NLRP3 at multiple points, reduces IL-1β and IL-18 release, and crosses the blood–brain barrier. The Co-ALS trial demonstrated acceptable safety and tolerability of colchicine in ALS patients. Chitotriosidase-1 (CHIT1) plasma levels are validated as an accessible microglial activation biomarker. We propose a Phase 2b biomarker-stratified trial incorporating CHIT1, plasma neurofilament light (NfL), and plasma NLRP3 as stratification and outcome measures. Conclusions: Colchicine represents a biologically plausible, affordable, and safe candidate for repurposing in ALS via NLRP3 inhibition. The gap between mechanistic evidence and clinical design can be bridged by incorporating neuroinflammatory biomarkers into future trials. High-CHIT1 patients are predicted to derive maximum benefit and should be prioritised for recruitment.